Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C@H:12]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:23][C:15]2[C:16]3[CH:17]=[N:18][NH:19][C:20]=3[CH:21]=[CH:22][C:14]=2[CH2:13]1.[CH3:32][N:33]1[C:37]2([CH2:46][CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[C:42]([C:47](O)=[O:48])[CH:43]=3)[CH2:38]2)[C:36](=[O:50])[NH:35][C:34]1=[O:51].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:29][C:28]([CH3:31])([CH3:30])[CH2:27][N:24]1[C:25](=[O:26])[C@H:12]([NH:11][C:47]([C:42]2[CH:43]=[C:44]3[C:39](=[CH:40][CH:41]=2)[CH2:38][C:37]2([C:36](=[O:50])[NH:35][C:34](=[O:51])[N:33]2[CH3:32])[CH2:46][CH2:45]3)=[O:48])[CH2:13][C:14]2[CH:22]=[CH:21][C:20]3[NH:19][N:18]=[CH:17][C:16]=3[C:15]=2[CH2:23]1
Reactant: CC(C)(C)CN1Cc2c(ccc3[nH]ncc23)C[C@@H](N)C1=O
Reactant: CN1C(=O)NC(=O)C12CCc1cc(C(=O)O)ccc1C2
Agent: CS(=O)(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1C(=O)NC(=O)C12CCc1cc(C(=O)N[C@@H]3Cc4ccc5[nH]ncc5c4CN(CC(C)(C)C)C3=O)ccc1C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 7-(R)-amino-9-(2,2-dimethylpropyl)-6,7,9,10-tetrahydro-3H-2,3,9-triazacyclohepta[e]inden-8-one bis-methanesulfonate (110 mg, 0.23 mmol) [Chaturvedula et al. WO 2006/052378], (±)-3-methyl-2,5-dioxo-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-6′-carboxylic acid (77 mg, 0.28 mmol) [Bell et al. WO 2004/082605], HOBT (43 mg, 0.28 mmol), and EDC (54 mg, 0.28 mmol) in DMF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (2×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]([C:20]1[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=1)([F:19])[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:28]=[O:29].CO>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]([C:20]1[CH:21]=[C:22]([NH:26][C:28]([NH:27][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:29])[CH:23]=[CH:24][CH:25]=1)([F:19])[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(C(F)(F)COCCCCCCOCc2ccccc2)c1
Reactant: CCOC(=O)CN=C=O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)Nc1cccc(C(F)(F)COCCCCCCOCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.8 %

Procedure:
To a solution of Intermediate 58 (3.9 g, 10.7 mmol) in methylene chloride (35 mL) was added ethyl isocyanatoacetate (1.38 mL, 12.3 mmol). The mixture was stirred at room temperature for 5 hours. The crude reaction was cooled to 0° C. and then methanol (2.3 mL) was added. The mixture was stirred at room temperature for 0.5 hours and the solvent was removed under reduced pressure. Purification by column chromatography using methylene chloride/methanol (from pure methylene chloride to 98:2) as eluent gave the title compound (5.1 g, 95%) as oil.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH:4]([CH3:9])[C:5](=[O:8])[CH2:6][CH3:7].Br[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1.[Mg]>>[ClH:18].[Cl:18][C:14]1[CH:13]=[C:12]([C:5]([OH:8])([CH2:6][CH3:7])[CH:4]([CH3:9])[CH2:3][N:2]([CH3:10])[CH3:1])[CH:17]=[CH:16][CH:15]=1
Reactant: Clc1cccc(Br)c1
Reactant: CCC(=O)C(C)CN(C)C
Agent: [Mg]
Product: CCC(O)(c1cccc(Cl)c1)C(C)CN(C)C
Product: Cl
Yield: 19 %

Procedure:
63 g of crude mixture were obtained under the conditions cited for Example 1 from 38.0 g (270 mmole) 1-dimethylamino-2-methylpentan-3-one, 74.7 g (390 mmole) 1-bromo-3-chlorobenzene and 9.50 g (390 mmole) magnesium turnings. This mixture was introduced on to a 7×45 cm column packed with silica gel and eluted with 7:1 diisopropyl ether/methanol. 12.8 g of base were obtained, from which 10.8 g of hydrochloride (4) (14% theoretical) with a melting point of 160-162° C. were obtained with trimethylchlorosilane/water in 2-butanone/ether.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[CH:3]3[OH:14])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: CC1(C)Oc2ccc(C#N)cc2C(N2CCN(c3ccc(F)cc3)CC2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 1-(4-fluoro-phenyl)-piperazine as starting material, the title compound was prepared as a white solid.
Reaction SMILES: [OH:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1>Cl.CCOCC>[F:24][C:21]([F:22])([F:23])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:2]1([OH:1])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2C(F)(F)F)CC1
Agent: Cl
Solvent: CCOCC
Product: OC1(c2ccccc2C(F)(F)F)CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
tert-Butyl 4-hydroxy-4-[2-(trifluoromethyl)phenyl]piperidine-1-carboxylate (0.40 g, 1.0 mmol) was dissolved in a 2.0 M solution of HCl in ether (5 mL). After being stirred at room temperature overnight, the solution was diluted with ether. The white solid was filtered and washed with ether to give 170 mg of pure product. MS calculated for C12H14F3NO: (M+H) 246; found 246.1.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[N:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][C:11]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:41]([N:43]1[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2[N:45]=[C:44]1[NH2:52])[CH3:42].C(N(CC)CC)C>CN(C=O)C.O>[CH2:41]([N:43]1[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2[N:45]=[C:44]1[NH:52][C:16]([C:13]1[CH:14]=[CH:15][C:10]2[N:9]=[C:8]3[C:2](=[O:1])[NH:3][CH2:4][CH2:5][CH2:6][N:7]3[C:11]=2[CH:12]=1)=[O:18])[CH3:42]
Reactant: CCn1c(N)nc2ccccc21
Reactant: O=C(O)c1ccc2nc3n(c2c1)CCCNC3=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1c(NC(=O)c2ccc3nc4n(c3c2)CCCNC4=O)nc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.1 %

Procedure:
A solution of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]benzimidazole-8-carboxylic acid (Intermediate B, 103 mg, 0.42 mmol) and TBTU (149 mg, 0.46 mmol) in DMF (2 mL) is stirred for 10 min. 1-Ethyl-1H-benzimidazol-2-amine (68 mg, 0.42 mmol) and triethylamine (43 mg, 0.42 mmol) are added and the reaction is stirred at room temperature for 16 h. The reaction mixture is diluted with H2O. A yellow solid is formed that is filtered and washed with EtOAc and a small amount of methanol to afford the title compound (85 mg, 51%).
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[OH:14])[C:9]#[N:10].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C(O)(=O)C>O1CCCC1>[C:9]([C:8]1[CH:11]=[CH:12][C:13]([OH:14])=[C:6]([NH:5][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:7]=1)#[N:10]
Reactant: N#Cc1ccc(O)c(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(C#N)ccc2O)CC1
Temperature: 100 °C
Yield: 86.8 %

Procedure:
Polymer supported sodium cyanoborohydride (3531 mg, 7.20 mmol, 2.04 mmol/g) was added to a solution of 3-amino-4-hydroxybenzonitrile (D19, 477 mg, 3.56 mmol), 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (709 mg, 3.56 mmol) and acetic acid (1 mL, 17.5 mmol) in tetrahydrofuran (10 mL). The mixture was heated by microwave at 100° C. for 30 min and then for a further 30 min before being filtered and concentrated by rotary evaporation to give 1,1-dimethylethyl 4-[(5-cyano-2-hydroxyphenyl)amino]-1-piperidinecarboxylate (D32, 982 mg, 3.09 mmol, 87% yield) as a yellow solid.
Reaction SMILES: [CH3:1][Mg]Cl.[CH2:4]([C:6]1[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[CH:11]=[N:10][C:9]=2[NH:8][C:7]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=1)[CH3:5]>C1COCC1>[CH2:4]([C:6]1[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[CH:11]=[N:10][C:9]=2[NH:8][C:7]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([OH:26])([CH3:1])[CH3:25])=[CH:20][CH:19]=1)[CH3:5]
Reactant: CCc1c(-c2ccc(C(C)=O)cc2)[nH]c2ncc3nccn3c12
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CCc1c(-c2ccc(C(C)(C)O)cc2)[nH]c2ncc3nccn3c12
Temperature: -20 °C
Yield: 50.5 %

Procedure:
MeMgCl (3 M in THF, 0.54 mL, 1.6 mmol) was added to THF (3 mL) then cooled to about −20° C. 1-(4-(1-Ethyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-2-yl)phenyl)ethanone (0.062 g, 0.204 mmol) was suspended in THF (3 mL) then added to the MeMgCl solution with stirring while maintaining the temperature of the mixture at about −15 to −20° C. The flask with the 1-(4-(1-ethyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-2-yl)phenyl)ethanone was rinsed with THF (2 mL) then this solution was also added to the MeMgCl mixture. The mixture was stirred for about 10 min then AcOH (1 mL) was added. The material was purified in two equal portions by preparative reverse phase HPLC (Table 2, method j). The fractions from the preparative HPLC containing the title compound were concentrated under reduced pressure to remove most or all of the 1,4-dioxane. The mixture was basified with saturated aqueous NaHCO3 and the solids collected by filtration. The material was dried overnight under vacuum at about 60° C. to give 2-(4-(1-ethyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-2-yl)phenyl)propan-2-ol (0.033 g, 51%): LC/MS (Table 2, Method a) Rt=1.85 min; MS m/z 321 (M+H)+. Syk IC50=B
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Li]CCCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:3][CH:4]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Clc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
4-Bromochlorobenzene (3.2 g, 16.62 mmol) was dissolved in dry THF (20 mL). After bringing the reaction temperature down to -78° C. with an acetone/dry ice bath, nBuLi (15.58 mL, 1.6M, 1.5 equiv.) was added slowly and stirred at -78° C. for 30 min. Tributyltinchloride (6.77 mL, 1.5 equiv.) was added and stirred overnight while bringing the reaction to room temperature. Reaction mixture was quenched by stirring the reaction flask open in air for 1 hour after which THF was rotavaporated off. Product was obtained as an oil (7.35g, 97%) after passing the mixture through a quick silica gel column eluting with 100% hexanes.
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[C:8]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)=[N:7][O:6][CH:5]=2)[CH3:2].[N+](=[CH2:17])=[N-]>CCOCC>[CH2:1]([C:3]1[C:4]2[C:8]([C:9]([CH3:17])=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)=[N:7][O:6][CH:5]=2)[CH3:2]
Reactant: CCc1cc([N+](=O)[O-])cc2nocc12
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CCc1cc([N+](=O)[O-])c(C)c2nocc12
Reaction time: 16 h

Procedure:
A solution of 4-ethyl-6-nitro-anthranil, (1.5 gm, 0.0577 mol.) in anhydrous ether (50 ml) was mixed with an ethereal solution of diazomethane (100 ml, conc. 1 gm CH2N2 /80 ml) and stirred for 16 hrs. The excess diazomethane was removed by pouring the reaction mixture over a short column of silica gel and eluting the column with ether. The ethereal solution was evaporated to give a yellow solid and this solid was purified by column chromatography (40% methylene chloride: pet. ether 30-60) to yield 4-ethyl-7-methyl-6-nitro-anthranil as a solid. The solid was recrystallized from 10% ether: pet ether 30-60, Yield: 1.145 gm. mp. 68°-69° C., IR (CHCl3): 2980, 1625, 1550, 1460 cm-1. H-NMR (CDCl3): 1.40 (t, 3H, CH3), 2.80 (s, 3H, CH3), 2.90 (q, 1H, CH2), 7.30 (br. s, 1H, H5), 9.30 (s, 1H, H3).
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:17][CH3:18])[CH2:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[CH3:3].S(Cl)([Cl:21])=O>>[ClH:21].[CH2:2]([N:4]([CH2:17][CH3:18])[CH2:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([Cl:1])=[O:11])[CH3:3]
Reactant: CCN(CC)CCOc1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Agent: Cl
Product: CCN(CC)CCOc1ccccc1C(=O)Cl

Procedure:
Reaction of 2-(2-diethylaminoethoxy)benzoate hydrochloride with thionyl chloride as described in the procedure of Example 6 gives 2-(2-diethylaminoethoxy)benzoyl chloride hydrochloride.
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[CH:22]1([CH2:25][C:26]([C:29]2[O:30][C:31]([CH3:34])=[N:32][N:33]=2)([NH2:28])[CH3:27])[CH2:24][CH2:23]1>>[CH:22]1([CH2:25][C:26]([NH:28][C:12]([C:9]2[CH:8]=[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:18])([F:20])[F:19])[C:6]([C:2]3([F:1])[CH2:5][O:4][CH2:3]3)=[CH:11][N:10]=2)=[O:14])([C:29]2[O:30][C:31]([CH3:34])=[N:32][N:33]=2)[CH3:27])[CH2:24][CH2:23]1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1(F)COC1)C(F)(F)F
Reactant: Cc1nnc(C(C)(N)CC2CC2)o1
Product: Cc1nnc(C(C)(CC2CC2)NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3(F)COC3)cn2)o1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxylic acid (example 142b) and 1-cyclopropyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-amine (example 173b) as starting materials and isolated (70 mg, 46%); MS (ESI, m/z): 473.5 (M+H+).
Reaction SMILES: [C:1](C(C)(CCCC)C(O)=O)(OCC)=O.ClCCl.F.[F:19][C:20]([F:32])([F:31])[CH:21]([CH2:27][CH2:28][CH2:29][CH3:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CCCCC>[F:19][C:20]([F:31])([F:32])[C:21]([CH3:1])([CH2:27][CH2:28][CH2:29][CH3:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCCCC(C)(C(=O)O)C(=O)OCC
Reactant: CCCCC(C(=O)OCC)C(F)(F)F
Agent: F
Solvent: CCCCC
Solvent: ClCCl
Product: CCCCC(C)(C(=O)OCC)C(F)(F)F
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a 90 ml. stainless steel bomb was added 6.6 g. of 2-carboethoxy-2-methylhexanoic acid, 5 ml. of dichloromethane, and 0.4 ml. of 48% hydrofluoric acid. The bomb was sealed with an assembly consisting of a rupture disk (2400-3600 psig) and a needle valve. The bomb was then cooled in a dry ice-acetone bath and evacuated to less than 10 mmHg pressure. Sulfur tetrafluoride (15 g.) was condensed into the bomb from an attached lecture bottle. The needle valve was closed and the bomb was stored in a hood at room temperature for 3 days. After this time, the bomb was immersed to 1/3 of its length in a 60° C. bath. After warming at 60° C. for 3 days, the bomb was cooled and vented. The residual materials were taken up in pentane (250 ml.). The pentane solution was dried (NaF/MgSO4), filtered and distilled to give 3.14 g. (42%) of ethyl 2-trifluoromethylhexanoate, b.p. 79°-81° /20 mmHg.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[C:20]1[C:21]([C:26]([OH:28])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:30](F)(F)S(OC1C=CC([N+]([O-])=O)=CC=1C(OCC1C=CC=CC=1)=O)(=O)=O.[N+](=C)=[N-]>C(O)(=O)C>[CH2:1]([O:8][C:9]([C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[C:20]1[C:21]([C:26]([O:28][CH3:30])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1-c1ccc([N+](=O)[O-])cc1C(=O)OCc1ccccc1
Reactant: O=C(OCc1ccccc1)c1cc([N+](=O)[O-])ccc1OS(=O)(=O)C(F)(F)F
Agent: C=[N+]=[N-]
Solvent: CC(=O)O
Product: COC(=O)c1ccccc1-c1ccc([N+](=O)[O-])cc1C(=O)OCc1ccccc1

Procedure:
To a solution of 2′-benzyloxycarbonyl-4′-nitro-2-biphenylcarboxylic acid (2.8 g) which was prepared by the same procedure as a series of reaction of Reference Example 4→Reference Example 5, using Benzyl 2-trifluoromethylsulfonyloxy-5-nitrobenzoate, in ether-ethyl acetate (1:1, 40 ml), diazomethane (30 ml) was added. Acetic acid was added to the reaction mixture, and the solution was concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:2) to give the title compound (2.57 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[N:13][C:14](F)=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.C([N:27](C(C)C)CC)(C)C>CN1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[N:13][C:14]([NH2:27])=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Fc1ccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)cn1
Agent: CN1CCCC1
Product: Nc1ccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)cn1
Temperature: 135 °C

Procedure:
A mixture of 2-chloro-6-(6-fluoropyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidine, about four equivalents of a primary or secondary amine (R═H, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl, or C1-C20 heteroaryl), and about two eq. diisopropylethylamine in N-methylpyrrolidine (˜0.1M) is heated to about 130-140° C. in a sealed microwave reactor for 10-40 min, followed by removal of volatiles under high vacuum. The crude mixture is purified by flash chromatography to give intermediate 2-chloro-6-(6-aminopyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidine, which may be Suzuki coupled with a monocyclic heteroaryl, fused bicyclic heterocycle or heteroaryl boronate reagent following General Procedure A.
Reaction SMILES: C[O-].[Na+].[CH3:4][CH:5]([C:7]1[CH:11]=[CH:10][O:9][C:8]=1[C:12]([O:14]C)=O)[CH3:6].[CH3:16][NH:17][CH3:18]>CO>[CH3:16][N:17]([CH3:18])[C:12]([C:8]1[O:9][CH:10]=[CH:11][C:7]=1[CH:5]([CH3:6])[CH3:4])=[O:14]
Reactant: CNC
Reactant: COC(=O)c1occc1C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1ccoc1C(=O)N(C)C

Procedure:
A solution of sodium methoxide (3.3 g) and 3-(1-methylethyl)-2-furancarboxylic acid, methyl ester (14 g) in dry methanol (50 ml) was treated with dimethylamine gas during 2 hours. The solvent was removed in vacuo and the residue was dissolved in diethyl ether (150 ml) and washed with water (100 ml). The ethereal extract was dried over anhydrous sodium sulphate and evaporation of the solvent gave the title compound (12 g) as an oil.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[C:11]([O-])([O-])=[O:12].[K+].[K+].C(N1CCCCCC1=O)O>>[CH2:11]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:1]1=[O:8])[OH:12]
Reactant: O=C([O-])[O-]
Reactant: O=C1CCCCCN1
Agent: C=O
Agent: O=C1CCCCCN1CO
Agent: [K+]
Product: O=C1NCCCCC1CO
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1,130 g (10.00 mol) of 6-caprolactam, 306.1 g (10.00 mol) of 98% purity paraformaldehyde and 6.91 g (0.05 mol) of ground K2CO3 were brought to reaction. Apart from the catalyst, a clear solution was present. After 2 hours, the mixture was cooled to 50° C.; a few grains of pure N-methylol-caprolactam were added as seed crystals. 1,428 g of methylolcaprolactam (=99.9% of the theoretical yield) were obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=O)[CH:16]=[CH:17][CH:18]=1.[H][H]>C(OCC)(=O)C.[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: O=C(C=Cc1cccc(OCc2ccc3ccccc3n2)c1)c1ccc(O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1ccc(CCCc2cccc(OCc3ccc4ccccc4n3)c2)cc1

Procedure:
A solution of 4-(3-(3-(2-quinolinylmethyloxy)phenyl)-1-oxo-2-propen-1-yl)phenol (0.008 mol) in ethyl acetate (150 ml) is shaken under 50 psi of hydrogen gas in the presence of 10% palladium on carbon catalyst (1.0 g). The reaction mixture is filtered through a celite pad and evaporated to give 4-(3(3-(2-quinolinylmethyloxy)phenyl)propyl)phenol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[N:2]=1.CS[C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17]>>[N+:16]([NH:15][C:14]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:3]1[N:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[NH:19])([O-:18])=[O:17]
Reactant: NCCNCc1cccnn1
Reactant: CSC(=N)N[N+](=O)[O-]
Product: N=C(NCCNCc1cccnn1)N[N+](=O)[O-]

Procedure:
Reacting N-(3-pyridazinylmethyl)ethylenediamine with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(3-pyridazinylmethylamino)ethyl]guanidine. Treatment with hydrobromic acid gives the hydrobromide salt.
Reaction SMILES: [H-].[Na+].ICCO[CH:7]([O:9][CH2:10][CH2:11][I:12])[CH3:8].[C:13]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>O1CCCC1>[CH2:22]([O:21][C:13](=[O:20])[C:14]([CH2:19][CH2:18][O:17][CH2:8][CH2:7][O:9][CH2:10][CH2:11][I:12])([CH2:14][CH2:15][O:16][CH2:8][CH2:7][O:9][CH2:10][CH2:11][I:12])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:23]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(OCCI)OCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCOCCOCCI)(CCOCCOCCI)C(=O)OCC
Temperature: 25 °C
Yield: 75 %

Procedure:
1.71 g (0.036 mol) of sodium hydride was added to 40 ml of tetrahydrofuran dried over metallic sodium, and to this solution was added dropwise a mixed solution of 17.6 g (0.048 mol) of bis(2-iodoethoxy)ethane and 1.92 g (0.012 mol) of diethyl malonate, the mixture being refluxed under heating for hours. Tetrahydrofuran was distilled off and the residue was cooled to room temperature, added with 1N hydrochloric acid until the litmus paper came to indicate acidity and then extracted three times with 50 ml of ether. After drying the extract over anhydrous sodium sulfate, ether was distilled off and the oily residue was passed through a silica gel-packed column and eluted with petroleum ether-ether (2:1) to obtain 2.90 g of 2,2-bis(8-iodo-3,6-dioxaoctyl)malonic acid diethyl ester, (ICH2CH2OCH2CH2OCH2CH2)2 -C(CO2Et)2 (yield: 38%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1.[CH3:17][CH:18]1[CH2:22][CH2:21][CH2:20][NH:19]1.C(=O)([O-])[O-].[K+].[K+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)C>[CH3:3][CH:4]([OH:5])[CH3:10].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[CH3:11][N:9]1[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5][CH:4]([CH2:3][CH2:2][N:19]2[CH2:20][CH2:21][CH2:22][CH:18]2[CH3:17])[CH2:10]1
Reactant: CC1CCCN1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=S
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)O
Product: CC1CCCN1CCC1CN(C)C(=S)c2cccnc2O1
Reaction time: 8 h
Yield: 32.8 %

Procedure:
To a suspension of 5.0 g (0.019 mole) of 2-(chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thione in 25 ml of absolute ethanol was added 3.5 g (0.04 mole) of 2-methylpyrrolidine. The mixture was heated to reflux for 6.5 hr and left standing at room temperature overnight. Mass spec and TLC showed presence of starting materials. Approximately 5 g of potassium carbonate was added and heating at reflux was continued for 24 hr. Ethanol was removed by rotary evaporation (70° C., 30 mm). The residue was taken up in 100 ml of methylene chloride and washed with 2×50 ml dil. aqueous sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation (70° C., 30 mm). The residual syrup was dissolved in isopropyl aocohol and treated with fumaric acid affording 4.5 g (0.01 mole, 49.2%) of crude crystals. Two recrystallizations from isopropyl afforded 1.5 g (16.4%) of yellow crystals, m.p., 92°-95° C.