Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[F:29])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:21]([F:29])[CH:22]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: Fc1cc(Br)c2cn[nH]c2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Fc1cc(Br)c2cnn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 40.3 %

Procedure:
To a solution of 4-bromo-6-fluoro-1H-indazole (1.0 g, 4.65 mmol) in dichloromethane (50 mL) was added 4-benzyloxy-3-fluorobenzeneboronic acid (2.29 g, 9.31 mmol), pyridine (0.75 mL, 9.28 mmol), copper acetate (1.26 g, 6.96 mmol) and powdered 4A molecular sieves (2 g). The reaction mixture was stirred at room temperature in the presence of air for 4 days. Celite was added to the mixture and stirred for 5 mins, then the mixture was filtered through a pad of celite and then the filtrate was washed with water, dried over magnesium sulphate, filtered and concentrated. The product was purified by silica gel chromatography eluting with 5-100% dichloromethane in hexane to yield the title compound (D7) (779 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.4 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (49.9 mg, 42%).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH3:12])[C:7](=[S:11])[CH:8]([CH3:10])[O:9][C:4]=2[CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:19]=[C:20]([F:23])[C:21]=1F.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:15][C:16]1[CH:17]=[C:18]([C:24]([F:25])([F:26])[F:27])[CH:19]=[C:20]([F:23])[C:21]=1[O:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH3:12])[C:7](=[S:11])[CH:8]([CH3:10])[O:9][C:4]=2[CH:3]=1
Reactant: CC1Oc2cc(O)ccc2N(C)C1=S
Reactant: Fc1cc(C(F)(F)F)cc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC1Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc2N(C)C1=S
Temperature: 80 °C
Reaction time: 1 h

Procedure:
First, 7-hydroxy-2,4-dimethyl-2H-1,4-benzoxazine-3 (4H)-thione (0.2 g) and 3-chloro-4,5-difluorotrifluoromethylbenzene (0.3 g) were dissolved in DMSO (5 ml), potassium carbonate (0.2 g) was added thereto, and the mixture was stirred at 80° C. for one hr. Water (10 ml) was added thereto to terminate the reaction, and the reaction mixture was extracted with ethyl acetate (20 ml×2), washed with water and a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo, and the residue was purified by silica gel chromatography (developing solvent: n-hexane/ethyl acetate=5/1) to prepare the title compound (0.2 g) as a colorless crystal.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[O:25])[N:9]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:10]3([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:3]=12.[H-].[Na+].I[CH3:29].O>O1CCCC1>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:9]2[C:10]3([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:3]3[C:2](=[O:1])[CH:7]=[CH:6][N:5]([CH3:29])[C:4]=3[C:8]2=[O:25])=[CH:22][CH:21]=1
Reactant: COc1ccc(CN2C(=O)c3nccc(O)c3C23CCCCC3)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)c3c(c(=O)ccn3C)C23CCCCC3)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 4′-hydroxy-6′-(4-methoxybenzyl)spiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridin]-7′(6′H)-one (1.0 mmol, 1 eq) in tetrahydrofuran (25 mL), add sodium hydride (2.5 mmol, 2.5 eq) at 0° C. and stir for 20 min. Add iodomethane (2.5 mmol, 2.5 eq) to the above mixture and stir for 16 h. After completion add water to the reaction and extract with ethyl acetate. Remove the solvent under reduced pressure to get the crude which is purified by column chromatography to give 6′-(4-methoxybenzyl)-1′-methylspiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridine]-4′,7′(1′H,6′H)-dione (6).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1>N1C=CC=CC=1.C(Cl)Cl.C(Cl)Cl>[C:5]1([O:4][C:2](=[O:3])[NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cccnc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cccnc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Phenyl chloroformate (0.733 mL, 5.84 mmol) is suspended in pyridine/DCM (3 mL, 2:1). The solution is stirred at 0° C., and 3-aminopyridine (500 mg, 5.31 mmol) dissolved in DCM (1 mL) is added dropwise. The reaction mixture is at 0° C. for 1 hour. The solvent is removed in vacuo and the residue is dissolved in ethyl acetate. This organic portion is washed with 0.1 M HCl and then concentrated in vacuo to afford the titled compound. (MH+215)
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[CH:12]=[CH:13][C:14]([C:16]([O:18]C)=[O:17])=[CH:15][N:3]12.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O>C(O)(C)(C)C>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=[C:7]1[C:6]2[N:5]=[C:4]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:3]3[C:2](=[O:1])[C:11]=2[CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)c1ccc2nc3c(c(=O)n2c1)CCCC3
Reactant: COc1ccccc1C=O
Solvent: CC(C)(C)O
Product: COc1ccccc1C=C1CCCc2c1nc1ccc(C(=O)O)cn1c2=O
Yield: 31.4 %

Procedure:
1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, methyl ester (2.5 g) was reacted with 2-methoxy-benzaldehyde (2.6 g) in tert.butanol (75 ml) in the presence of potassium tert.butylate (4.3 g) under stirring at reflux temperature for 8 hours. After cooling the solution was concentrated in vacuo to a small volume and the precipitate was filtered and washed with little methanol and then dissolved in water containing NaHCO3 : the solution was acidified with 23% HCl to pH=4 and the precipitate was filtered and washed with water until neutral. Crystallization from acetone gave 1.1 g of 4-(2-methoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, m.p. 300° C. (dec.), N.M.R. (CDCl3 -CF3COOD) δp.p.m.: 1.93 (m) (2H,C-2 protons), 2.84 (m) (4H, C-1 and C-3 protons), 3.81 (s) (3H, --OCH3), 6.80-7.50 (m) (4H, phenyl protons), 7.70 (bs) (1H, =CH--), 8.17 (d) (1H, C-6 proton), 8.69 (dd) (1H, C-7 proton), 9.73 (d) (1H,C-9 proton).
Reaction SMILES: [C:1]1([OH:12])[C:10]2[C:5](=[CH:6][C:7](O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.[C:23](=[O:26])([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:12][C:1]2[C:10]3[C:5](=[CH:6][C:7]([O:26][C:23]4[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: Oc1ccc2c(O)cccc2c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(Oc4ccc([N+](=O)[O-])cc4)cccc3c2)cc1

Procedure:
232.7 g of 1,6-naphthalene diol, 409.5 g of 4-fluoronitrobenzene and 402.1 g potassium carbonate were combined with 1 1. of dimethylacetamide (DMAc) and heated to reflux for 1 hour to form 1,6-bis-(4-nitrophenoxy) naphthalene. The mixture was concentrated by distilling off 500 ml of DMAc. The mixture was cooled to room temperature and the product precipitated by pouring into 1 1. of water. A light tan solid was collected and washed with three 500 ml portions of methanol to facilitate drying.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C@@H:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][CH2:14]I)[CH:3]=1.[CH3:22][C:23]1[N:24]=[CH:25][C:26]([CH2:29][NH2:30])=[N:27][CH:28]=1.C(N(CC)CC)C>CS(C)=O>[ClH:1].[ClH:1].[Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C@@H:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][CH2:14][NH:30][CH2:29][C:26]2[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][N:27]=2)[CH:3]=1
Reactant: Cc1cnc(CN)cn1
Reactant: N#Cc1cc(F)c(Cl)cc1O[C@H](CCI)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cnc(CNCC[C@@H](Oc2cc(Cl)c(F)cc2C#N)c2ccccc2)cn1
Product: Cl

Procedure:
4-Chloro-5-fluoro-2-{[(1R)-3-iodo-1-phenylpropyl]oxy}benzonitrile (200 mg, 0.48 mmol), 5-methyl-2-pyrazinemethanamine (120 mg, 0.96 mmol) and triethylamine (335 μl, 2.4 mmol) were stirred in DMSO (5 ml) for 48 h. The mixture was washed with water and purified by chromatography (5% 1M ammonia-methanol/dichloromethane). The eluent was evaporated and the residue treated with 4M hydrogen chloride in dioxan (5 ml). The solvent was evaporated, azeotroped twice with toluene and triturated with ether to give the required product as a white solid.
Reaction SMILES: [C:1]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:23][C:24]1[S:25][C:26]([CH2:29][OH:30])=[N:27][N:28]=1.Cl>N1C=CC=CC=1>[OH:30][CH2:29][C:26]1[S:25][C:24]([NH:23][S:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:14][CH:15]=2)(=[O:21])=[O:20])=[N:28][N:27]=1
Reactant: Nc1nnc(CO)s1
Reactant: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(CO)s2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 73 %

Procedure:
To a solution of 4-decanamidobenzenesulfonyl chloride (435 mg, 1.26 mmol) in pyridine (5 mL) was added 2-amino-5-hydroxymethyl-1,3,4-thiadiazole (150 mg, 1.15 mmol). The reaction mixture was stirred at room temperature for 4.5 h, then 2 M HCl (15 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×30 mL). The organic extracts were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (70-230 mesh) eluted with CH2Cl2:methanol 9:1 to give the product as a solid, mp 69-70° C., in 73% yield (370 mg, 0.84 mmol); 1H NMR (300 MHz, DMSO-d6) δ 0.84 (t, 3H, J=7.2 Hz), 1.23 (m, 12H), 1.54-1.57 (m, 2H), 2.29 (t, 2H, J=7.5 Hz), 4.57 (d, 2H, J=4.8 Hz), 6.08 (t, 1H, J=5.0 Hz), 7.73 (m, 4H), 10.22 (s, 1H), 14.01 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 14.6, 22.8, 25.6, 30.0, 29.4, 29.5, 29.6, 31.9, 37.1, 59.1, 119.3, 127.6, 136.1, 143.5, 161.7, 168.1, 172.6; MS (LCQ, ESI+) Calcd for C19H29N4O4S2 441.2, found 441.1 (M+H)+; HRMS (ESI+, m/z) Calcd for C19H29N4O4S2 441.1630, found 441.1624 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH3:11])([O-:3])=[O:2].[CH3:12]OC(OC)N(C)C.N1CCCC1.Cl.[NH2:26][NH:27][C:28]([NH2:30])=[O:29].Cl>O>[CH3:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[CH2:11][CH:12]=[N:26][NH:27][C:28]([NH2:30])=[O:29]
Reactant: NNC(N)=O
Reactant: COC(OC)N(C)C
Reactant: Cc1cccc([N+](=O)[O-])c1C
Agent: Cl
Solvent: C1CCNC1
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1CC=NNC(N)=O
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
3-Nitro-ortho-xylene (1.77 ml, 13.23 mmol, 1.0 eq.) was combined with dimethylformamide dimethyl acetal (2.11 ml, 15.88 mmol, 1.2 eq.) dimethylformamide (7.35 ml, 1.8M) and pyrrolidine (1.32 ml, 15.88 mmol, 1.2 eq.) and heated at 110° C. for 8 hours. The reaction was then cooled to room temperature and concentrated. The residue was dissolved in dimethylformamide (7.35 ml, 1.8M) and treated at room temperature with a solution of semicarbazide-hydrochloride (1.55 g, 13.89 mmol, 1.05 eq.) in concentrated hydrochloric acid (1.2 ml, 14.55 mmol, 1.1 eq.) and water (16.5 ml, 0.8M). The mixture was stirred at room temperature for 30 minutes, cooled to 0° C. and filtered. The precipitate was washed with water (30 ml), cold ethanol (15 ml) and ethyl ether (25 ml) and then dried in vacuo to provide the title A compound (2.44 g).
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([CH:7]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[O:8]1)=[O:6])[CH3:3].[C:18]1(O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+].C1OCCOCCOCCOCCOCC[O:29]C1>C(#N)C>[OH:29][CH:7]([CH:9]([O:8][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[C:5]([NH:4][CH:2]([CH3:1])[CH3:3])=[O:6]
Reactant: COc1cccc(C2OC2C(=O)NC(C)C)c1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cccc(C(Oc2ccccc2)C(O)C(=O)NC(C)C)c1

Procedure:
This compound was prepared from N-(1-methylethyl)-3-(3-methoxyphenyl)-2-oxiranecarboxamide (14.3 g.), phenol (6.0 g.), sodium hydride (50% oil dispersion, 3.2 g.), 18-crown-6 (1.8 g.), and acetonitrile (500 ml.) as described in Example 12. The compound obtained as an oil was used directly in the subsequent reaction.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:27]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(N2CCCCC2)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(N2CCCCC2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(piperidin-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.61 min.; [M+H]+: 409.25 g/mol.
Reaction SMILES: [CH3:1][OH:2].[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[C:6](F)[N:5]=1.C[O-].[Na+].CO>C(Cl)(Cl)Cl>[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[C:6]([O:2][CH3:1])[N:5]=1
Reactant: CO
Reactant: Nc1nc(F)c(F)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1nc(N)c(F)cc1F
Temperature: 70 °C

Procedure:
To 1 ml of methanol were added 500 mg of 2-amino-3,5,6-trifluoropyridine together with 800 mg of 28% sodium methoxide/methanol solution, and the mixture was stirred at 70° C. for 3 and half hours, and allowed to cool. After adding 25 ml of chloroform, the mixture was washed with 5 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title product.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:23][C:10]2[CH:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:9]=2[CH:8]=1.[CH3:24][S:25]SC>CCCCCC.O1CCCC1>[CH3:16][N:13]1[CH2:14][CH2:15][C:9]2[CH:8]=[C:7]([S:25][CH3:24])[S:23][C:10]=2[CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1
Reactant: CSSC
Reactant: CN1CCc2cc(Br)sc2C(c2ccccc2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1cc2c(s1)C(c1ccccc1)CN(C)CC2
Temperature: 25 °C

Procedure:
A solution of n-butyl lithium in n-hexane (1.6M, 0.75 ml) was added dropwise to a stirred solution of 2-bromo-6-methyl-8-phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (0.40 g hydrobromide salt converted to free base by aqueous ammonia/dichloromethane extraction) in dry tetrahydrofuran (10 ml) cooled to -70° under nitrogen. After 10 minutes at -70° dimethyl disulphide (0.11 ml) was added dropwise and the mixture allowed to warm to room temperature. After 30 minutes the solution was evaporated, water (10 ml) added to the residue and extracted with dichloromethane (2×5 ml). The extracts were dried, filtered and evaporated to a pale yellow solid. Recrystallisation twice from n-hexane (4 ml) gave white needles (m.p. 90°) of the title product.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[C:16](Cl)(=[O:19])[CH2:17][CH3:18].O>CN(C)C1C=CN=CC=1.ClCCl>[C:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][CH:11]=1)(=[O:19])[CH2:17][CH3:18]
Reactant: Oc1ccc(Br)cc1
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCC(=O)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (219 ml) was added to a solution of 4-bromophenol (259 g) and 4-dimethylaminopyridine (1.5 g) in dichloromethane (1000 ml) at 0° C. at such a rate that the temperature did not rise above 20° C. When the addition was complete propionyl chloride (137 ml) was added in portions over 1 hour such that the temperature did not rise above 20° C. Finally, the mixture was stirred at room temperature for 2 hours. Water (700 ml) was added and the layers were separated. The dichloromethane solution was washed with brine (500 ml), dried (MgSO4) and concentrated in vacuo to give the title compound as an oil, 344 g.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.O=[C:19]([CH2:26][CH2:27][CH3:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[N:1]1[S:2][N:3]=[C:4]2[C:9]([CH:10]3[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH2:26][CH2:27][CH3:28])[NH:12][C:13]4=[N:14][NH:15][CH:16]=[C:17]34)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Nc1cc[nH]n1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: O=Cc1cccc2nsnc12
Product: CCCC1=C(C(=O)OCC)C(c2cccc3nsnc23)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2,1,3-benzothiadiazole-4-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [PH2:1](=[O:3])[OH:2].[CH2:4]([O:6][CH:7](OCC)[O:8][CH2:9][CH3:10])[CH3:5].F[C:15](F)(F)[C:16](O)=O>>[CH2:4]([O:6][CH:7]([PH:1](=[O:2])[O:3][CH2:15][CH3:16])[O:8][CH2:9][CH3:10])[CH3:5]
Reactant: O=[PH2]O
Reactant: CCOC(OCC)OCC
Reactant: O=C(O)C(F)(F)F
Product: CCOC(OCC)[PH](=O)OCC
Yield: 62.9 %

Procedure:
Using the procedure described in Example 1b, 3.3 parts of commercially available 50% aqueous phosphinic acid solution are reacted with 22.25 parts of triethylorthoformate in the presence of 0.57 parts of trifluoroacetic acid. Work up and purification by the procedures described in Example 1b gives 3.1 parts (62.9%) of ethyl diethoxymethylphosphinate of 94.7% purity.
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]-1,6-dihydro-5-hydroxy-8-methylbenzo[1,2-b:4,3-b']dipyrrol-3(2H)-yl]carbonyl]-1,6-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.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:13][C:12](=[O:14])[C:11]1(Cl)Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C>C(O)(=O)C.[Zn]>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:13][C:12](=[O:14])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(COCc2ccccc2)C1(Cl)Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C1CC(COCc2ccccc2)C1
Temperature: 60 °C

Procedure:
Zinc dust (93.5 g, 1.44 mol) was added to a solution of 3-(benzyloxymethyl)-2,2-dichlorocyclobutanone (124 g, 0.48 mol) in glacial acetic acid (800 ml) at room temperature. The reactants were heated at 60° C. for 1 hr, after which time dry diethyl ether was added to the cooled products, which were then filtered. The residue was washed with diethyl ether and the combined filtrate and washings were concentrated under reduced pressure. The residue was dissolved in dichloromethane, which was washed with saturated NaHCO3 twice and water once. The organic phase was dried over MgSO4 and the solvent was evaporated to give an oily product, which was purified by column chromatography (Hexane: EtOAc=6:1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([CH3:17])[CH:11]=1.O.C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+].O>[Br:1][C:15]1[CH:16]=[C:10]([F:9])[CH:11]=[C:12]([CH3:17])[C:13]=1[NH2:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)ccc1N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(F)cc(Br)c1N
Reaction time: 8 h

Procedure:
A solution of N-bromosuccinimide (18.7 g, 0.105 mol) in 70 mL of N,N-dimethylformamide was added dropwise to a solution of 4-fluoro-2-methylaniline in 70 mL of N,N-dimethylformamide at 20° C. The reaction mixture was stirred overnight. The dark solution was poured into a mixture of water (1000 mL), brine (50 mL) and ethyl acetate (300 mL). The mixture was transferred into a separatory funnel, shacked and separated. The aqueous phase was extracted with ethyl acetate (4×150 mL). The combined organic layers were washed with water (5×100 mL), brine (2×100 mL), dried with sodium sulfate, filtered and concentrated. The 1H NMR spectrum of the crude material showed at least 95% purity. The product was further purified on silica gel pad (eluent system ethyl acetate/n-hexane: 1/8). The pure fractions were combined and evaporated to give 14.9 g of product. The impure fractions were combined, concentrated, redissolved in diethyl ether (30 mL) and extracted with 5% hydrochloric acid (5×10 mL). The acidic phase was basified with aq. potassium hydroxide and extracted with diethyl ether to provide 0.8 g of the title compound. Total yield was 15.7 g (77%).