Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([C:14]2[S:21][C:20]([CH3:22])=[C:19]3[C:15]=2[CH2:16][C@H:17]2[C:23]([CH3:25])([CH3:24])[C@H:18]23)=[O:13])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>C(O)(C)C.[OH-].[Na+].C(OCC)C>[CH3:9][C:6]1[CH:5]=[C:4]([CH2:10][CH2:11][C:12]([C:14]2[S:21][C:20]([CH3:22])=[C:19]3[C:15]=2[CH2:16][C@H:17]2[C:23]([CH3:25])([CH3:24])[C@H:18]23)=[O:13])[CH:3]=[C:2]([CH3:1])[C:7]=1[O:8][CH2:26][CH:28]1[CH2:29][O:30]1
Reactant: ClCC1CO1
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOCC
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCC1CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.3 %

Procedure:
A solution of 3-(3,5-dimethyl-4-hydroxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (2.00 g, 5.64 mmol, Intermediate 10) in isopropanol (20 mL) and 3 N aq. NaOH (12 mL) is treated with epichlorohydrine (2.12 g, 16.92 mmol). The dark red reaction mixture is stirred at rt for 18 h. The mixture is diluted with diethyl ether (250 mL) and washed with sat. aq. NaHCO3 followed by water. The organic layer is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (1.72 g, mixture of diastereoisomers) as a pale yellow oil; LC-MS: tR=1.16 min, [M+1]+=411.17; 1H NMR (CDCl3): δ 6.85 (s, 2H), 4.04-3.97 (m, 1H), 3.77-3.69 (s, 1H), 3.52-3.44 and 3.38-3.32 (2m, 1H), 3.05-2.84 (m, 6H), 2.79 (d, J=18.8 Hz, 1H), 2.72-2.68 (m, 1H), 2.38 (s, 3H), 2.26 (s, 6H), 1.92-1.86 (m, 2H), 1.11 (s, 3H), 0.71 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:22][N:23]1[C:27]([CH3:28])=[C:26]([C:29](O)=[O:30])[C:25](=[O:32])[N:24]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[OH:19][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([O:6][C:5]3[CH:20]=[CH:21][C:2]([NH:1][C:29]([C:26]4[C:25](=[O:32])[N:24]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:23]([CH3:22])[C:27]=4[CH3:28])=[O:30])=[CH:3][CH:4]=3)=[CH:8][CH:9]=[N:10]2)=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: COc1cc2c(Oc3ccc(N)cc3)ccnc2cc1O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1O
Temperature: 60 °C
Reaction time: 10 h
Yield: 93.6 %

Procedure:
To a solution of 4-(4-aminophenoxy)-6-methoxyquinolin-7-ol (3.61 g, 12.8 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (2.85 g, 12.27 mmol) in DMF (50 mL) was added EDCI (2.81 g, 14.66 mmol) and HOAT (0.33 g, 2.4 mmol). The reaction was stirred at 60° C. for 10 hours, cooled to room temperature and diluted with H2O (200 mL). The solid was collected by filtration and dried in vacuo at 60° C. overnight to give the title compound as a white solid (5.7 g, 89.9%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:25]=1.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[F:33]>>[CH2:9]1[O:8][C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]2[CH:25]=[C:2]([C:29]3[CH:30]=[CH:31][C:32]([F:33])=[C:27]([Cl:26])[CH:28]=3)[CH:3]=[CH:4][C:5]=2[NH:11][C:10]1=[O:12]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: O=C1COC(c2ccccc2)(c2ccccc2)c2cc(Br)ccc2N1
Product: O=C1COC(c2ccccc2)(c2ccccc2)c2cc(-c3ccc(F)c(Cl)c3)ccc2N1

Procedure:
Prepared from 7-bromo-5,5-diphenyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-chloro-4-fluoro benzeneboronic acid generally according to the coupling procedure described in example 1. 1H NMR (DMSO-d6): δ 10.17 (s, 1H), 7.65 (dd, J=8.3, 2.44 Hz, 1H), 7.50 (dd, J=7.32, 2.44 Hz, 1H), 7.34-7.43 (m, 7H), 7.25 (d, J=8.3 Hz, 1H), 7.22-7.24 (m, 1H), 7.16-7.19 (m, 4H), 6.75 (d, 1.95 Hz, 1H), 4.26 (s, 2H); MS (ESI) m/z 442/444 ([M−H]−); Anal. calcd for C27H19ClFNO2: C, 73.06; H, 4.31; N, 3.16. Found: C, 72.67; H, 4.36; N, 2.89.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N:16]3[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]3[CH3:22])=[C:12]([Cl:15])[CH:13]=2)[NH:8][C:7](=[O:23])[C:6]1=[O:24])([OH:3])=O.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[CH2:25]([NH:32][C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N:16]3[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]3[CH3:22])=[C:12]([Cl:15])[CH:13]=2)[NH:8][C:7](=[O:23])[C:6]1=[O:24])=[O:3])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1ccc(C)n1-c1cc2[nH]c(=O)c(=O)n(CC(=O)O)c2cc1Cl
Reactant: NCc1ccccc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(C)n1-c1cc2[nH]c(=O)c(=O)n(CC(=O)NCc3ccccc3)c2cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
1.3 g (3.7 mmol) of 1-(carboxymethyl)-7-chloro-6-(2,5-dimethyl-1-pyrrolyl)-2,3(1H,4H)-quinoxalinedione and 1.6 ml (12.3 mmol) of benzylamine were dissolved in 30 ml of dimethylformamide and, at 0° C., a solution of 0.89 ml (4.1 mmol) of diphenylphosphoryl azide in 10 ml of dimethylformamide was added dropwise. The mixture was stirred at room temperature for 16 h and then poured into ice-water, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: toluene/acetone=1:1) to yield 1.1 g (67%) of the product.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[O:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1>C(Cl)Cl>[Br:1][CH2:2][CH2:3][O:4][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1
Reactant: C1=COCCC1
Reactant: OCCBr
Solvent: ClCCl
Product: BrCCOC1CCCCO1
Reaction time: 18 h
Yield: 50.8 %

Procedure:
To a solution of 2-bromoethanol (10.00 g, 80 mmol) and 3,4-dihydro-2H-pyran (10.1 g, 120 mmol) in CH2Cl2 (400 mL) was added a spatula of Amberlyst-15 ion exchange resin and the reaction was stirred for 18 hrs. It was then filtered through Celite and concentrated. Distillation (40 mm Hg, b.p.=102° C.) afforded tetrahydro-2-(2-bromoethoxy)-2H-pyran (8.49 g).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]2[C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=[C:6]2[C:5]21[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2.[CH:22]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][C:27]=1[O:35][CH3:36])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH:22]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:19]2[CH2:20][CH2:21][C:5]3([N:4]([CH3:3])[CH2:9][CH2:8][N:7]4[C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=[C:6]34)[CH2:17][CH2:18]2)=[O:31])=[CH:28][C:27]=1[O:35][CH3:36])([CH3:24])[CH3:23]
Reactant: CN1CCn2c(C(F)(F)F)ccc2C12CCNCC2
Reactant: COc1cc(C(=O)O)ccc1OC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCC3(CC2)c2ccc(C(F)(F)F)n2CCN3C)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2′-methyl-6′-(trifluoromethyl)-3′,4′-dihydro-2′H-spiro[piperidine-4,1′-pyrrolo[1,2-a]pyrazine]dihydrochloride (69 mg, 0.20 mmol), 4-isopropoxy-3-methoxybenzoic acid (42 mg, 0.20 mmol), HATU (76 mg, 0.20 mmol), Et3N (112 μL, 0.80 mmol) and DMF (2 mL) was allowed to stir at room temperature for 3 h. The mixture was filtered and purified by reverse-phase preparatory HPLC (10-99% ACN/water). The desired fractions were concentrated to give (4-isopropoxy-3-methoxyphenyl)(2′-methyl-6′-(trifluoromethyl)-3′,4′-dihydro-2′H-spiro[piperidine-4,1′-pyrrolo[1,2-a]pyrazine]-1-yl)methanone as an amorphous white solid. ESI-MS m/z calc. 465.2, found 466.3 (M+1)+; Retention time: 1.23 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.01 (d, J=1.7 Hz, 1H), 6.97 (dd, J=8.2, 1.7 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.53 (d, J=3.0 Hz, 1H), 5.94 (d, J=3.5 Hz, 1H), 4.57 (dt, J=12.2, 6.1 Hz, 1H), 4.52 (s, 1H), 3.99 (s, 2H), 3.87 (s, 3H), 3.69 (s, 1H), 3.40 (s, 1H), 3.34 (t, J=5.4 Hz, 3H), 2.39 (s, 3H), 2.11 (s, 2H), 1.82 (s, 2H), 1.38 (d, J=6.1 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].Br[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16].[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]
Reactant: O=C(CBr)N1CCOCC1
Reactant: COC(=O)c1ccc(Br)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)c(OCC(=O)N2CCOCC2)c1
Temperature: 80 °C
Yield: 14.5 %

Procedure:
Methyl 4-bromo-3-hydroxybenzoate (71 mg) and 4-(bromoacetyl)morpholine (71 mg) were combined in DMF (5 ml). Sodium hydride (14 mg, 60% dispersion in mineral oil) was added and the reaction heated at 80° C. under nitrogen for 16 hours. The reaction was quenched with water (2 ml) and solvent the evaporated in vacuo. The residue was partitioned between water (10 ml) and ethyl acetate/chloroform (1:1, 2×10 ml). The organic layers were combined, dried using a hydrophobic filter and evaporated under vacuum. The residue was partially purified by SPE (2 g, Si), eluting with a methanol/chloroform gradient (0.5% to 5%), and the product fractions further purified by mdap, to give methyl 4bromo-3{[2-(4-morpholinyl)-2-oxoethyl]oxy}benzoate as a white solid (16 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:11])=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.C(N(CC)CC)C.[C:20]([Si:22]([CH3:25])([CH3:24])[CH3:23])#[CH:21]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:21]#[C:20][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]([NH2:11])=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1nc(C2CC2)c(Br)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(Br)c(C2CC2)nc1N
Reaction time: 5 h

Procedure:
Cuprous iodide (11.23 mg, 0.059 mmol) was added to a mixture of 5-bromo-6-cyclopropyl-3-iodopyridin-2-amine (1 g, 2.95 mmol), triethylamine (13.4 g, 132.75 mmol) and THF (4 mL) and the resultant mixture was purged with nitrogen gas. Ethynyltrimethylsilane (347.7 mg, 3.54 mmol) and Pd(PPh3)2Cl2 (41.36 mg, 0.059 mmol) were added and purged with argon. The resultant mixture was stirred under argon atmosphere for 5 hours. The mixture was concentrated to residue. Residue was dissolved in ethyl acetate, washed with water, brine and dried over sodium sulfate and concentrated to get solid which was further purified on column (SiO2) using 15% ethyl acetate in hexane as eluent. This afforded 1.2 g (crude) of the pure compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:4].S(=O)(=O)(O)O.[CH2:24]=O>CC(O)=O>[N+:14]([C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][N:5]([C:3](=[O:4])[C:2]([F:17])([F:18])[F:1])[CH2:24]2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: C=O
Reactant: O=C(NCCc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(N1CCc2ccc([N+](=O)[O-])cc2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.6 %

Procedure:
2,2,2-Trifluoro-N-[2-(4-nitrophenyl)ethyl]acetamide (21.9 g, 83.4 mmol) was dissolved in HOAc (80 mL) and sulfuric acid (120 mL) and paraformaldehyde (4.0 g, 125 mmol) were added at rt. The solution was stirred at rt for 24 h. The reaction was poured cautiously into approximately 1 L of ice with stirring. The resulting suspension of brown sludge was extracted into EtOAc. The organic was washed with saturated aqueous NaHCO3, brine and dried over MgSO4. The solvent was removed and the brown solid was triturated with hexanes. The brown solid was dried under vacuum and provided 15 g (66%) of the desired tetrahydroisoquinoline product. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J=27.0 Hz, 1H), 8.05 (m, 1H), 7.47 (d, J=8.5 Hz, 1H), 4.88 (d, J=18.1 Hz, 2H), 3.81 (m, 2H), 3.06-2.97 (m, 2H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:6][C:7]([CH:10]([F:12])[F:11])=[CH:8][CH:9]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[F:11][CH:10]([F:12])[C:7]1[O:6][C:5]([CH2:4][NH2:1])=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=NCc1ccc(C(F)F)o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(C(F)F)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a solution of 2-(azidomethyl)-5-(difluoromethyl)furan (0.50 g, 2.92 mmol) in a mixture of tetrahydrofuran (10 mL) and water (1 mL) was added triphenylphosphine (1.15 g, 4.39 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The solvent was removed in vacuo and the residue was purified on strong cation exchange column to afford (5-(difluoromethyl)furan-2-yl)methanamine as a yellow oil in 70% yield (0.30 g): MS (ES+) m/z 3148.2 (M+1).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]([O:10][C:11]([N:13]1CCC[C:16](=O)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH2:15][CH2:16][C:3](=[CH2:4])[CH2:2][CH2:1]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 1 g methyltriphenylphosphoniumbromide (MW: 357.22, 2.79 mmol) in 20 ml of tetrahydrofuran was treated at −78° C. with 1.22 ml of a 2.3 M n-butyl lithium solution in N-hexane (2.8 mmol). The reaction mixture was stirred at −78° C. for ten minutes, then at 0° C. for one hour. The yellow suspension was cooled to −78° C. and treated with a solution of 595 mg 4-oxo-azepane-1-carboxylic acid tert-butyl ester (WO 2000044376) (MW: 213.279, 2.78 mmol) in 10 ml tetrahydrofuran. The reaction mixture was stirred at room temperature for one and half hour. The reaction mixture was quenched with 30 ml of a saturated aqueous solution of ammonium chloride, diluted with 30 ml of ethyl acetate. The organic layer was successively washed with 30 ml water and 30 ml brine, dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue purified by chromatography over silica. (cyclohexane:ethyl acetate 1:1). Yield: 487 mg, 83%. NMR (CDCl3): 1.35 ppm (s, 9H, tert-but.); 1.6 ppm (m, 2H, —CH2—), 2.14 ppm (m, 2H), 2.33 ppm (m, 2H); 3.29 ppm (m, 4H, N—CH2); 4.67 ppm (m, 2H, vinyl-CH2).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.C1C(=O)N([Br:25])C(=O)C1.O>CN(C=O)C>[Br:25][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:8]([CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[CH2:9][CH2:10][CH2:11]2
Reactant: CN1CCC(N2CCCc3ccccc32)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(N2CCCc3cc(Br)ccc32)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 1-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroquinoline (500 mg, 2.17 mmol) in 7 mL of DMF was cooled to 0° C. then treated dropwise with NBS (386 mg, 2.17 mmol) in 7 mL DMF. The reaction was stirred at 0° C. for 2 hours then treated with 30 mL H2O. The suspension was extracted with 100 mL EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give a dark residue, which was filtered through a short plug of silica gel using 5%, 2M NH3 in MeOH/CH2Cl2 (100 mL). The filtrate was concentrated and subjected to flash chromatography on silica gel using 5% MeOH/CH2Cl2 then 5% 2M NH3 in MeOH/CH2Cl2. A light yellow oil was obtained (490 mg, 73.0%). 1H-NMR (CDCl3) δ: 7.10 (dd, J=2.1, 10.8 Hz), 7.04-7.03 (m, 1H), 6.50 (d, J=9.0 Hz, 1H), 3.57-3.47 (m, 1H), 3.18 (t, J=5.7 Hz, 2H), 2.98-2.94 (m, 2H), 2.68 (t, J=6.0 Hz, 2H), 2.31 (s, 3H), 2.10-2.02 (m, 2H), 1.91-1.69 (m, 6H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:19](Cl)(=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]>C1COCC1.[NH4+].[Cl-].C(OCC)(=O)C>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:19](=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CCCCC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A solution of 4(S)-(−)-benzyl-2-oxazolidinone (10 g, 56.43 mmol) in anhydrous THF (200 ml) at −78° C. was treated with a 2.5M solution of n-butyl lithium in hexanes (23.70 ml, 59.26 mmol) with stirring. The reaction mixture was allowed to stir at −78° C. for 30 min before valeryl chloride (7.57 ml, 62.10 mmol) was added. The reaction mixture was then allowed to warm to ambient temperature over 15 h after which it was diluted with NH4Cl solution, diluted with ethyl acetate and washed with brine. The organic phase was dried (Na2SO4) and concentrated to give a gum. This was purified by flash chromatography (10% EtOAc in 40/60 hexanes) to give the sub-title compound (14.61 g, 99%) as a colourless oil: 1H NMR (400 MHz, CDCl3) δ 0.94-1.20 (3H, m), 1.35-1.50 (2H, m), 1.62-1.80 (2H, m), 2.74-2.84 (1H, m), 2.86-3.08 (2H, m), 3.27-3.39 (1H, m), 4.11-4.26 (2H, m), 4.62-4.76 (1H, m), 7.18-7.40 (5H, m).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[CH3:16][N:17]([CH2:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1)[CH3:18].[H-].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:18][N:17]([CH2:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][CH2:3][CH:2]([OH:1])[CH2:4][N:5]1[C:6](=[O:15])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]1=[O:14])[CH3:16]
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Reactant: CN(C)Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CN(C)Cc1cccc(OCC(O)CN2C(=O)c3ccccc3C2=O)c1
Yield: 39.5 %

Procedure:
A solution of 2-(oxiranylmethyl)-1H-isoindole-1,3-(2H)-dione (20.3 g) and 3-(dimethylaminomethyl)phenol (22.3 g) in dimethylformamide (200 ml) with a catalytic amount of sodium hydride (0.2 g) was heated for 6 h at 100° under N2. The solvent was evaporated to give an oil which was dissolved in chloroform and washed with 2N sodium hydroxide and water. The organic solution was evaporated to give an oil (14 g). A portion of the oil (0.8 g) was distilled to give the title compound (0.6 g) as an oil, b.p. 250° (0.08 mmHg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([Br:12])=[CH:10][N:9]=[C:8]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:17]=[CH:18][CH:19]=2)[N:7]=1.CCN(C(C)C)C(C)C.[CH2:37]([S:40](Cl)(=[O:42])=[O:41])[CH2:38][CH3:39]>ClCCl.CN(C1C=CN=CC=1)C>[Br:12][C:11]1[C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][S:40]([CH2:37][CH2:38][CH3:39])(=[O:42])=[O:41])=[N:7][C:8]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:17]=[CH:18][CH:19]=2)=[N:9][CH:10]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)ncc1Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)ncc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a solution of N-(3-((4-((3-aminopropyl)amino)-5-bromo-2-pyrimidinyl)amino)phenyl)-1-pyrrolidinecarboxamide (150 mg, 0.30 mmol) in dichloromethane (4 mL) was added DIEA (0.16 mL, 0.92 mmol) and DMAP (1.4 mg, 0.011 mmol) at 0° C., then a solution of 1-propanesulfonyl chloride (51 mg, 0.36 mmol) in dichloromethane (5 mL) was added. The resulting reaction mixture was stirred at 0° C. for 1 h and at room temperature overnight. The reaction mixture was concentrated. Purification by HPLC using acetonitrile/water gave the title compound (67 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][O:10][CH3:11].[Cl:12][C:13]1[CH:34]=[CH:33][C:16]([CH2:17][NH:18][C:19]([C:21]2[C:22]([OH:32])=[C:23]3[CH:29]=[C:28]([CH2:30][OH:31])[S:27][C:24]3=[N:25][CH:26]=2)=[O:20])=[CH:15][CH:14]=1>CN(C=O)C.O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][NH:18][C:19]([C:21]2[C:22](=[O:32])[C:23]3[CH:29]=[C:28]([CH2:30][OH:31])[S:27][C:24]=3[N:25]([CH2:8][CH2:9][O:10][CH3:11])[CH:26]=2)=[O:20])=[CH:33][CH:34]=1
Reactant: COCCBr
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CO)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)sc21
Temperature: 25 °C

Procedure:
Potassium carbonate (5.0 g) and bromoethylmethyl ether (5.0 g) are added to a solution of N-(4-chlorobenzyl)-4-hydroxy-2-(hydroxymethyl)thieno[2,3-b]pyridine-5-carboxamide (11.4 g, prepared as described in U.S. Pat. No. 6,239,142) in anhydrous DMF (350 mL). The reaction mixture is stirred at room temperature for 18 b. The mixture is diluted with water (600 mL) and filtered. The resulting white powder is dried in a vacuum oven to afford 8.44 g of the title compound as a white solid. Physical characteristics. M.p. 193° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.58, 8.65, 7.37, 7.29, 5.82, 4.70, 4.54, 4.47, 3.76, 3.24. HRMS (FAB) m/z 407.0836 (M+H)+. Anal. Found: C, 55.81; H, 4.71; N, 6.90; Cl, 8.58, S, 7.81.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3]1.[H-].[Na+].F[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]>CN(C=O)C>[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[CH2:3]1
Reactant: CN1CCC(CO)C1
Reactant: N#Cc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(COc2cccc(C#N)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(1-Methylpyrrolidin-3-yl)methanol (0.500 g, 4.34 mmol) was dissolved in dry DMF (8 mL), cooled (<0° C.), NaH (0.260 g, 6.51 mmol, 55% in oil) added and stirred for 30 minutes. 3-Fluorobenzonitrile (0.552 g, 4.56 mmol) was added and the reaction mixture allowed to warm to r.t. over 1 h. Due to excessive foaming the reaction mixture was diluted with dry DMF to 20 mL and stirred over night at r.t. The reaction was quenched by addition of water portionwise, and the mixture was extracted with DCM. The organic phase was dried over a phase separator and concentrated in vacuo. The product was purified by flash chromatography using a step gradient of EtOAc:MeOH:TEA (100:10:2) in EtOAc to give the title compound as an oil. Yield: 0.573 g (58%). 1H NMR (400 MHz, CDCl3) δ 7.30-7.35 (m, 1H), 7.18-7.22 (m, 1H), 7.09-7.12 (m, 1H), 7.07-7.09 (m, 1H), 3.86 (d, 2H, J=6.95 Hz), 2.54-2.67 (m, 3H), 2.40-2.51 (m, 2H), 2.33 (s, 3H), 2.00-2.10 (m, 1H), 1.51-1.61 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:3]1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[N:18]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:9][C:4]=2[CH2:3]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC1CCC(=O)C(CC(=O)c2ccccn2)C1
Product: CC1CCc2c(cc(-c3ccccn3)n2-c2ccc(C(=O)O)cc2)C1
Yield: 65 %

Procedure:
Following the general methods as outlined under Intermediate 13, starting from 4-methyl-2-(2-oxo-2-pyridin-2-ylethyl)cyclohexanone and 4-aminobenzoic acid, the title compound was isolated in 65% yield (96% purity by HPLC). MS(ESI+): 333.5; MS(ESI−): 331.6.