Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[C:20]12([CH2:30][C:31](O)=[O:32])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>>[C:20]12([CH2:30][C:31]([NH:1][N:2]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:19])=[O:32])[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[CH2:21]1)[CH2:29]2
Reactant: Nn1nc(-c2cccc(Cl)c2)c2ccccc2c1=O
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1nc(-c2cccc(Cl)c2)c2ccccc2c1=O

Procedure:
The product of Example 125A and 2-(adamantan-1-yl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO) δ 11.29 (s, 1H), 8.46-8.39 (m, 1H), 8.02-7.92 (m, 2H), 7.76-7.69 (m, 1H), 7.68-7.54 (m, 4H), 2.06 (s, 2H), 1.95 (s, 3H), 1.74-1.51 (m, 12H); MS (APCI) m/z 448 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11](NC3C=C(C=CC=3F)C(O)=O)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.S(Cl)(Cl)=O.[NH2:28][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][C:38]=1[CH3:39])[C:32]([O:34][CH3:35])=[O:33].N1C=CC=CC=1>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:28][C:29]3[CH:30]=[C:31]([CH:36]=[CH:37][C:38]=3[CH3:39])[C:32]([O:34][CH3:35])=[O:33])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: O=C(O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture comprising 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (Intermediate 1A step 3) (750 mg, 3.11 mmol) and thionyl chloride (5 ml, 68.5 mmol) under N2 was heated at reflux for 2 hrs. The mixture was concentrated in vacuo and azeotroped with toluene. Methyl 3-amino-4-methylbenzoate (514 mg, 3.11 mmol) (pre-dried at 45° C.) was added followed by pyridine (5 ml) and the mixture was stirred at room temperature under N2 overnight. The reaction mixture was diluted with EtOAc and washed with sat. NaHCO3, brine, H2O, dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica eluting with 50-100% EtOAc in iso-hexane afforded the title compound as an orange solid;
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.O=S(Cl)[Cl:19]>C(Cl)(Cl)Cl>[Cl:19][CH2:2][C:3]1[N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1
Reactant: CCOC(=O)Cn1nc([N+](=O)[O-])cc1CO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cn1nc([N+](=O)[O-])cc1CCl
Temperature: 0 °C
Reaction time: 3 h
Yield: 67.8 %

Procedure:
To a mixture of 146a (1.50 g, 6.55 mmol) in CHCl3 (60 mL) cooled at 0° C. was slowly added SOCl2 (2.34 g, 19.6 mmol) while maintaining the internal temperature below 5° C. This reaction mixture was warmed to 50° C. and stirred at this temperature for 3 h. It was then cooled to 0° C. and quenched with water. The organic layer was separated and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 146b (1.1 g, 68%) as a yellow solid. MS-ESI: [M+H]+ 247.9
Reaction SMILES: C([Li])CCC.C(NC1CCCCC1)(C)C.[CH:16]1([CH2:19][C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])[CH2:18][CH2:17]1.[F:27][C:28]1[CH:42]=[CH:41][C:31]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[O:33])=[CH:30][CH:29]=1>O1CCCC1>[CH:16]1([CH:19]([C:32]([C:31]2[CH:41]=[CH:42][C:28]([F:27])=[CH:29][CH:30]=2)([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[OH:33])[C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])[CH2:17][CH2:18]1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCCCOC(=O)CC1CC1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCOC(=O)C(C1CC1)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
Butyl lithium (5 mL of 2M solution, 10 mmol) was added to a solution of N-isopropylcyclohexylamine(1.4 g, 10 mmol) in 20 mL of tetrahydrofuran at -10° C. After stirring for 30 minutes and cooling to -70° C., butyl cyclopropaneacetate (1.5 g 10 mmol) was added. After stirring for an additional 30 minutes, 4,4'-difluorobenzophenone (1.1 g, 5 mmol) was added and the mixture stirred for 6 hours at -70° C. The mixture was quenched with 2N hydrochloric acid and extracted with diethyl ether. The extracts were dried and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 0.75% ethyl acetate in hexane to give 1.0 g of the title compound; m.p. =77°-80° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][N:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][N:7]=[N:8]2)=[C:4]([NH:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]nnc2n1
Reactant: NCc1ccccc1
Solvent: CCCCO
Product: Clc1nc(NCc2ccccc2)c2[nH]nnc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,6-Dichloro-8-azapurine (0.84 mmol), prepared as described in Example 17, was dissolved in n-butanol (4 ml) and benzylamine (1.4 mmol) was added. The reaction mixture was stirred at room temperature overnight. After concentration in vacuo the product was purified by chromatography (SiO2, IV—from 1% MeOH and 0.25% acetic acid to 2% MeOH with 0.35% acetic acid).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[C:14]([CH2:23][C:24]([O:26]C)=O)=[C:13]3[CH3:28])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:29][NH2:30]>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[C:14]([CH2:23][C:24]([NH:30][CH3:29])=[O:26])=[C:13]3[CH3:28])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: COC(=O)Cc1c(C)n(-c2ccnc3cc(Cl)ccc23)c2ccc(OC)cc12
Solvent: CO
Product: CNC(=O)Cc1c(C)n(-c2ccnc3cc(Cl)ccc23)c2ccc(OC)cc12

Procedure:
Methyl 1-(7-chloroquinol-4-yl)-5-methoxy-2-methylindol-3-ylacetate (1.7g.) in methanol (50ml.) containing 30% w/v methylamine solution (25ml.) was refluxed for 10 hours. The solvents were evaporated in vacuo and the residue crystallised from a 1:1 v/v mixture of benzene and cyclohexane to give 1-(7-chloroquinol-4-yl)-5-methoxy-N,2-dimethylindol-3-ylacetamide, m.p. 168°-169° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[N+:23]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)([O-:25])=[O:24]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[N+:23]([C:26]1[CH:31]=[C:30]([C:2]2[CH:7]=[C:6]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:3]=2)[CH:29]=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Nc1ccc(S(=O)(=O)c2cc(-c3cccc([N+](=O)[O-])c3)nc(N3CCCC3)c2)cc1
Yield: 48.1 %

Procedure:
A mixture of 191 mg (0.5 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 92 mg (0.55 mmole) 3-nitrophenylboronic acid, 18 mg bis(triphenylphosphine)-palladium(II)-chloride is refluxed for 2.5 hours in 7 ml toluene and 2 ml 2N aqueous potassium carbonate. The solvents are removed in vacuo. Flash chromatography (silicagel, ethyl acetate/hexane 1/1) of the residue yields 102 mg (48%) pure 4-[2-(3-nitro-phenyl)-6-pyrrolidine-1-yl-pyridine-4-sulfonyl]-phenylamine as a yellow solid mp.: 249-251° C.
Reaction SMILES: C[O-].[Na+].I.[NH:5]=[C:6]1[N:10]([CH3:11])[CH:9]=[CH:8][S:7]1.[C:12]1([N:18]=[C:19]=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:11][N:10]1[CH:9]=[CH:8][S:7][C:6]1=[N:5][C:19]([NH:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[S:20]
Reactant: S=C=Nc1ccccc1
Reactant: Cn1ccsc1=N
Agent: C[O-]
Agent: I
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cn1ccsc1=NC(=S)Nc1ccccc1

Procedure:
Sodium methoxide (5.40 g) was added to a stirred mixture of 2-imino-3-methylthiazoline hydroiodide (24.95 g) in ethanol (100 ml) and the mixture brought to reflux. Phenyl isothiocyanate (16.35 g) in toluene (50 ml) was added over 30 minutes and reflux continued for a further hour then cooled in ice. The solid obtained on filtration and washing with ethanol and water was dried to give the product, mpt 172.5°-173.5°. Recrystallisation from iso-propanol gave analytically pure product, mpt 173.5°-174°.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:21](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.N.CO>CN(C)C=O.C(OCC)(=O)C>[C:17]([C:14]1[C:13]2[NH:12][CH:11]=[CH:10][C:9]=2[C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:16][CH:15]=1)(=[O:19])[NH2:21]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)O)c2[nH]ccc12
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(C(N)=O)c2[nH]ccc12
Yield: 50.1 %

Procedure:
A solution of 4-(tert-butoxycarbonyl)-1H-indole-7-carboxylic acid (0.36 g, 1.38 mmol), HATU (0.30 g, 1.60 mmol), 4-methylmorpholine (0.75 mL, 6.89 mmol) and a 2M solution of ammonia in methanol (1.80 mL, 3.45 mmol) in dimethylformamide (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (150 mL) and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography chloroform: (10% ammonium hydroxide in methanol) 9:1 as eluent afforded tert-butyl 7-carbamoyl-1H-indole-4-carboxylate (0.18 g, 50%). 1H NMR (400 MHz, CDCl3): 10.50 (bs, 1H), 7.83 (d, 1H), 7.43 (m, 2H), 7.15 (m, 1H), 6.30 (bd, 2H), 1.62 (s, 9H). MS (EI) for C14H16N2O3: 259 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[C:18]([CH2:20][C:21](OCC)=[O:22])#[N:19].N1CCCCC1>C1(C)C=CC=CC=1>[CH3:9][O:8][C:6]1[CH:7]=[C:2]2[C:3]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:20]([C:18]#[N:19])[C:21](=[O:22])[NH:1]2)=[CH:4][CH:5]=1
Reactant: COc1ccc(C(=O)c2ccccc2)c(N)c1
Reactant: CCOC(=O)CC#N
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc2c(-c3ccccc3)c(C#N)c(=O)[nH]c2c1
Temperature: 300 °C
Yield: 28.8 %

Procedure:
A solution of (2-amino-4-methoxy-phenyl)-phenyl-methanone (400 mg, 1.76 mmol) and ethyl 2-cyanoacetate (239 mg, 225 μl) in toluene (6 ml) containing catalytic amounts of piperidine (15.0 mg, 17.4 μl) was pumped at a flow rate of 0.42 ml min−1 (residence time 40 min) through a steel reactor coil (volume=17 ml) that was heated to 300° C. The reaction mixture was evaporated to dryness and the remaining solid was triturated with CH2Cl2/heptane 2:1 for 3 h. The solid was filtrated off and washed two times with CH2Cl2/heptane 1:1 to give the title compound (140 mg, 29%) as off-white solid. MS (ESI): 277.4 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:12]([CH3:15])([CH3:14])[CH3:13])[S:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[Si:16]([O:23][CH2:24][C:25]1[C:30]([B:31]2[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]2)=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:40])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:12]([C:5]1[S:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:3]([CH2:2][NH:40][C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([B:31]3[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:38])([CH3:39])[O:32]3)[C:25]=2[CH2:24][O:23][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[N:4]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)c1sc(C(C)(C)C)nc1CBr
Reactant: CC1(C)OB(c2cccc(N)c2CO[Si](C)(C)C(C)(C)C)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1sc(C(C)(C)C)nc1CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1CO[Si](C)(C)C(C)(C)C
Temperature: 45 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
A suspension of 125a (1 g, 3.4 mmol), 2-((tert-butyldimethylsilyloxy)methyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine (125b) (1.1 g, 3.1 mmol) and cesium carbonate (1.3 g, 4.1 mmol) in acetonitrile (30 mL) was stirred at 45° C. overnight. The reaction mixture was filtered and the filtrate was concentrated at reduced pressure. The residue was purified on silica gel eluting with 0 to 1% EtOAc in petroleum ether to afford 125c as yellow oil (1.1 g, 56%). LCMS: (M+H)+ 575.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:28]=[CH:27][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][CH:22]([CH2:23][C:24]([OH:26])=[O:25])[C:15]4=[CH:14][C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:29]([F:32])([F:31])[F:30])([CH3:3])[CH3:2].C1C(=O)N([Cl:40])C(=O)C1>C(Cl)Cl>[Cl:40][C:14]1[C:13]2[CH:12]=[C:11]([O:10][CH2:9][C:8]3[CH:27]=[CH:28][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([C:29]([F:32])([F:30])[F:31])[CH:7]=3)[CH:19]=[CH:18][C:17]=2[N:16]2[CH2:20][CH2:21][CH:22]([CH2:23][C:24]([OH:26])=[O:25])[C:15]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1ccc(COc2ccc3c(c2)c(Cl)c2n3CCC2CC(=O)O)cc1C(F)(F)F
Reaction time: 0.25 h

Procedure:
To a solution of the 1st enantiomer (described as the enantiomer isolated and having the retention time of 29.8 min per the conditions reported in Example 1.25) of 2-(7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic Acid (0.049 mmol) in DCM (0.5 mL) at 0° C. was added NCS (0.049 mmol). The reaction was stirred for 15 minutes. The mixture was diluted with DCM and washed with water (twice) and saturated sodium thiolsulfate (aq). The organics were dried over Na2SO4, filtered, and concentrated to give the title compound as a yellow solid. LCMS m/z=482.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (d, J=6.06 Hz, 6H), 2.24-2.35 (m, 1H), 2.51-2.59 (m, 1H), 2.77-2.87 (m, 1H), 2.94 (dd, J=16.36, 4.11 Hz, 1H), 3.62-3.74 (m, 1H), 3.96-4.05 (m, 1H), 4.11-4.19 (m, 1H), 4.74-4.83 (m, 1H), 5.10 (s, 2H), 6.86 (dd, J=8.78, 2.34 Hz, 1H), 6.96 (d, J=2.40 Hz, 1H), 7.28 (d, J=8.72 Hz, 1H), 7.31 (s, 1H), 7.65-7.72 (m, 2H), 12.35 (bs, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][OH:11].C(=O)([O-])[O-].[K+].[K+].O.[NH2:19][C:20]1[N:29]=[C:28]([C:30]([N:32]2[CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[C:27]2[C:22](=[CH:23][CH:24]=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)[N:21]=1>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:19][C:20]1[N:29]=[C:28]([C:30]([N:32]2[CH2:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:40]2)=[O:31])[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:2]3[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=3[CH2:10][OH:11])[CH:26]=2)[N:21]=1
Reactant: OCc1cc(F)c(F)cc1Br
Reactant: CC1(C)OB(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CO)ccc2n1
Temperature: 120 °C

Procedure:
43 mg of (2-bromo-4,5-difluorophenyl)methanol, 80 mg of potassium carbonate, 4 μl of water and 16 mg of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride are added to a solution of 100 mg of [2-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone in 10 ml of ethanol under argon. The mixture is heated at 120° C. for 30 min; during which a precipitate forms. After cooling to 22° C., 10 ml of water are added, and the precipitate is filtered off. The residue is washed 3 times with 25 ml of ethanol each time and dried at 40° C. in vacuo.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[Se:10][C:6]=2[N:5]=[CH:4][N:3]=1.[CH3:15][S:16][C:17]1[S:18][C:19]([N+:23]([O-:25])=[O:24])=[C:20]([NH2:22])[N:21]=1.[OH-].[Na+]>CN(C=O)C>[CH3:15][S:16][C:17]1[S:18][C:19]([N+:23]([O-:25])=[O:24])=[C:20]([NH:22][C:2]2[C:7]3[C:8]4[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=4[Se:10][C:6]=3[N:5]=[CH:4][N:3]=2)[N:21]=1
Reactant: CSc1nc(N)c([N+](=O)[O-])s1
Reactant: Clc1ncnc2[se]c3c(c12)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CSc1nc(Nc2ncnc3[se]c4c(c23)CCCC4)c([N+](=O)[O-])s1

Procedure:
To a solution of 4-chloro-5,6,7,8-tetrahydrobenzo[1,2-b]pyrimidino[5,4-d]selenophene (420 mg, 1.57 mmol) in DMF (8 mL) was added sequentially 2-(methylthio)-5-nitrothiazol-4-amine (300 mg, 1.57 mmol) and powdered NaOH (180 mg, 4.71 mmol) at rt. Work-up as described in example 2, gave the product as a yellow color solid, mp 204-206° C. 1H NMR (400 MHz, CDCl3): δ 10.52 (1H, s, exchangeable with D2O, —NH), 8.73 (1H, s, H-2), 3.11 (2H, t, J=5.2 Hz, H-8), 2.98 (2H, t, J=5.0 Hz, H-5), 2.75 (3H, s, —SCH3), 1.92-1.98 (4H, m, H-6,7); 13C NMR (100 MHz, CDCl3): δ 176.9, 173.7, 152.2, 151.6, 151.1, 150.9, 142.7, 127.4, 124.1, 28.4, 28.0, 22.8, 22.5, 16.1; LC-MS (positive ion mode): m/z 426, 428 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:9]=[CH:10][C:3]=12.[NH3:24]>CCO>[NH2:24][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:9]=[CH:10][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: N
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(N)ncnc32)CC1
Temperature: 80 °C

Procedure:
A mixture of tert-butyl 4-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (4A-1; 0.050 g, 0.148 mmol) in saturated NH3 in EtOH (1 mL) was heated to 80° C. for 30 min. in the microwave. The mixture was cooled, concentrated, and dried in vacuo. Used without further purification. 1H-NMR (500 MHz, CDCl3) δ 8.38 (s, 1H), 7.93 (s, 1H), 5.60 (bs, 2H), 4.84-4.95 (m, 1H), 4.29 (bs, 2H), 2.95 (bs, 2H), 2.13-2.28 (m, 2H), 1.92-2.03 (m, 2H). LRMS m/z (M+H) Calcd: 319.1, found: 319.1.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][C:11]([NH:13][C@H:14]1[CH2:18][N:17](C(OC(C)(C)C)=O)[C@H:16]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)=[O:27])[CH2:15]1)=[O:12])=O)(C)(C)C>O1CCOCC1>[ClH:1].[ClH:1].[NH2:9][CH2:10][C:11]([NH:13][C@H:14]1[CH2:18][NH:17][C@H:16]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)[CH2:30][CH2:29]2)=[O:27])[CH2:15]1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)N2CCN(c3ccc(F)cc3)CC2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(=O)N[C@H]1CN[C@H](C(=O)N2CCN(c3ccc(F)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4 N hydrochloric acid in 1,4-dioxane (2.5 mL) was added to a solution of 1-[trans-4-(N-tert-butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-L-prolyl]-4-(4-fluorophenyl)piperazine (A, 83 mg) in 1,4-dioxane (2.5 mL) at room temperature. After stirring at room temperature for 30 min, the reaction mixture was evaporated in vacuo. The residue was washed with ether to give the titled compound (43 mg) as a white powder: 1H NMR (400 MHz, D2O) δ 2.51 (m, 1H), 2.63 (m, 1H), 3.48 (dd, J=4.4, 12 Hz, 1H), 3.57 (m, 4H), 3.82 (m, 1H), 3.85 (s, 2H), 3.93 (br s, 3H), 4.02 (m, 1H), 4.60 (br t, 1H), 5.08 (t, J=8.30 Hz, 1H), 7.28 (t, J=8.5 Hz, 2H), and 7.46 (m, 2H); mass spectrum (EI+) ine 349 (M).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:37]1[N:41]=[C:40]([NH2:42])[S:39][N:38]=1)[C:5]([NH:7][CH:8]1[C:35](=[O:36])[N:10]2[C:11]([C:32]([OH:34])=[O:33])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6]>C(O)=O>[CH3:1][O:2][N:3]=[C:4]([C:37]1[N:41]=[C:40]([NH2:42])[S:39][N:38]=1)[C:5]([NH:7][CH:8]1[C:35](=[O:36])[N:10]2[C:11]([C:32]([OH:34])=[O:33])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][CH2:23][NH2:24])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCNC(=O)OC(C)(C)C)CS[C@H]12)c1nsc(N)n1
Solvent: O=CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCN)CS[C@H]12)c1nsc(N)n1
Yield: 14.8 %

Procedure:
A solution of 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.0 g) in 99% formic acid (20 ml) was stirred for 2.5 hours at ambient temperature. The mixture was evaporated to dryness and the residue was dissolved in an aqueous solution of sodium bicarbonate and adjusted to pH 3 with 10% hydrochloric acid. A resulting precipitate was filtered off and the filtrate was subjected to column chromatography on non ion adsorption resin (Diaion HP 20) (Trademark: prepared by Mitsubishi Chemical Industries). The column was washed with water and eluted with 50% aqueous methanol. The eluate was evaporated to remove methanol and then lyophilized to give 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (250 mg). mp 200° to 205° C. (dec.)
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]34[C:12](=[CH:13][C:14](=[O:15])[C:5]=2[NH:4][CH:3]=1)[N:11]([C:16]([C:18]1[NH:26][C:25]2[C:20](=[C:21]5[CH2:32][CH2:31][N:30]([C:33]([C:35]6[NH:43][C:42]7[C:37](=[C:38]8[CH2:49][CH2:48][N:47]([C:50]([NH2:52])=[O:51])[C:39]8=[C:40]([OH:46])[C:41]=7[O:44][CH3:45])[CH:36]=6)=[O:34])[C:22]5=[C:23]([OH:29])[C:24]=2[O:27][CH3:28])[CH:19]=1)=[O:17])[CH2:10][CH:9]3[CH2:8]4.[C:53]([OH:56])(=[O:55])[CH3:54]>>[C:53]([O:56][CH2:8][CH:9]1[CH2:10][N:11]([C:16]([C:18]2[NH:26][C:25]3[C:24]([O:27][CH3:28])=[C:23]([OH:29])[C:22]4[N:30]([C:33]([C:35]5[NH:43][C:42]6[C:41]([O:44][CH3:45])=[C:40]([OH:46])[C:39]7[N:47]([C:50]([NH2:52])=[O:51])[CH2:48][CH2:49][C:38]=7[C:37]=6[CH:36]=5)=[O:34])[CH2:31][CH2:32][C:21]=4[C:20]=3[CH:19]=2)=[O:17])[C:12]2[CH:13]=[C:14]([OH:15])[C:5]3[NH:4][CH:3]=[C:2]([CH3:1])[C:6]=3[C:7]1=2)(=[O:55])[CH3:54]
Reactant: COc1c(O)c2c(c3cc(C(=O)N4CCc5c4c(O)c(OC)c4[nH]c(C(=O)N6CC7CC78C6=CC(=O)c6[nH]cc(C)c68)cc54)[nH]c13)CCN2C(N)=O
Reactant: CC(=O)O
Product: COc1c(O)c2c(c3cc(C(=O)N4CCc5c4c(O)c(OC)c4[nH]c(C(=O)N6CC(COC(C)=O)c7c6cc(O)c6[nH]cc(C)c76)cc54)[nH]c13)CCN2C(N)=O

Procedure:
In The Journal of Antibiotics, 1985, 38, 746, D. G. Martin et al reported that acetic acid adds across the spirocyclopropylcyclohexadienyl (SCPCH) system of CC-1065 to produce the phenolic, acetic acid product (AAP), 7-[[7-[[1-[(acetyloxy)methyl]-l,6-dihydro-5-hydroxy-8-methylbenzo[1,2-b:4,3-b']dipyrrol-3(2H)-yl]carbonyl]-l,6-dihydro-4-hydroxy-5-methoxybenzo[1,2-b:4,3-b']-dipyrrol-3(2H)-yl]carbonyl]-1,6-dihydro-4-hydroxy-5-methoxy-benzo[1,2-b:4,3-b']dipyrrole-3(2H)-carboxamide. AAP was tested in vitro and in vivo and found to be less potent than CC-1065 by a factor of 103 to 104 depending upon the particular test system and therefore tended to divert attention from adducts of the SCPCH system as useful antitumor agents or as prodrugs to CC-1065 analogs.