Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)#[CH:25]>>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]2[N:3]=[N:2][N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[CH:25]=2)=[CH:27][CH:28]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#Cc1ccc(OC)cc1
Product: COc1ccc(-c2cn(C3CCc4c(CC(=O)O)c5ccccc5n4C3)nn2)cc1

Procedure:
The title compound was prepared using analogous procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate and 1-ethynyl-4-methoxybenzene. 1H NMR (400 MHz, DMSO-d6): δ 12.14 (s, 1H), 8.67 (s, 1H), 7.78 (d, 2H), 7.48 (d, 1H), 7.42 (d, 1H), 7.13-6.99 (m, 4H), 5.40-5.30 (m, 1H), 4.74 (dd, 1H), 4.40 (dd, 1H), 3.80 (s, 3H), 3.61 (s, 2H), 3.12-3.01 (m, 2H). MS (+ESI) m/z: 403.1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([CH3:17])[O:8][N:7]=1.C1C(=O)N([Br:25])C(=O)C1.O.[K+].[Br-]>CN(C=O)C.CCCCCC.C(OCC)(=O)C>[Br:25][C:5]1[O:1][C:2]([C:6]2[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:9]([CH3:17])[O:8][N:7]=2)=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1onc(-c2ccco2)c1-c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1onc(-c2ccc(Br)o2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a solution of 3-(furan-2-yl)-4-phenyl-5-methylisoxazole (0.152 g, 0.670 mmol) in anhydrous DMF (6 ml), kept stirring at 0° C., is slowly added NBS (0.144 g, 0.810 mmol). A suspension is formed which is kept stirring for 2 h at ambient temperature. Water is then added, and then ethyl acetate. The two phases are separated and the aqueous phase is extracted three times with ethyl acetate. The total organic phase is first washed with a saline aqueous solution (NaCl) and then dried with anhydrous Na2SO4. The solvent is evaporated at reduced pressure. A yellow solid is obtained. When subjected to chromatography (silica gel, petroleum ether/ethyl acetate=9:1) it gave the product with 60% yield, as a white solid; m.p. 93-96° C. (hexane). FT-IR (KBr): 3143, 3055, 2962, 2923, 2851, 1632, 1605, 1505, 1434, 1408, 1236, 1202, 1122, 1019, 984, 921, 896, 796, 774, 721, 704, 676, 561 cm−1. 1H NMR (400 MHz, CDCl3, δ): 7.44-7.35 (m, 3H, aromatic protons); 7.26-7.23 (m, 2H, aromatic protons); 6.24 (d, 1H, J=3.3 Hz, furyl proton); 6.20 (d, 1H, J=3.3 Hz, furyl proton); 2.34 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 166.7, 152.1, 145.8, 129.9, 129.3, 128.7, 128.3, 124.1, 114.6, 113.8, 112.9, 11.1. GC-MS (70 eV) m/z (rel.int.): 305 [(M++2), 47], 303 (M+, 100), 264 (13), 263 (98), 262 (23), 261 (100), 234 (10), 232 (10), 154 (54), 153 (33), 129 (12), 127 (31), 77 (9), 43 (14). Anal. Calc. For C14H10BrNO2: C, 55.29; H, 3.31; N, 4.61. Found: C, 55.08; H, 3.60; N, 4.20.
Reaction SMILES: [C:1]([CH:9]1[CH2:13][O:12][C:11](=[O:14])[CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd](Cl)Cl>[CH2:1]([CH:9]1[CH2:13][O:12][C:11](=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(C(=O)c2ccccc2)CO1
Agent: Cl[Pd]Cl
Solvent: CO
Product: O=C1CC(Cc2ccccc2)CO1
Reaction time: 3 h
Yield: 54 %

Procedure:
To a solution of 4-benzoyl-dihydro-furan-2-one (5 g) in methanol (250 mL) in a Parr® reactor is added palladium chloride (0.25 g). The mixture is shaken under hydrogen (50 PSI) for 3 h. The mixture is filtered through a pad of Celite® (40 g) and the filtrate concentrated. The residue is chromatographed on SiO2 (10% ethyl acetate/hexanes, then 30% ethyl acetate/hexanes) to yield the title compound, (2.5 g, 34% from 3-benzoylpropionic acid), as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[Br:15]Br>C1COCC1>[Br:15][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[O:8][CH3:9]
Reactant: COc1cccc(F)c1
Reactant: BrBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(F)c1Br
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
The 3-fluoro anisole (15 g, 119 mmol) was placed in THF (300 mL) and cooled to about −78° C., and then n-BuLi (89 mL 1.6 M in hexanes) was added while maintaining the temperature at around −70° C. The mixture was stirred for about 15 minutes, and bromine (18.9 g, 119 mmol) was added over 10 minutes. The mixture was warmed to r.t. and stirred overnight. The mixture was quenched with water, diluted with ether (500 mL) and partitioned between water/ether (1/1 300 mL). The water layer was back extracted with ether (250 mL), and the combined organic fractions were dried, filtered and concentrated. The dark residue was distilled under house vacuum (product 115–130° C.) to recover about 13.8 g of the product as a gray oil (57%).
Reaction SMILES: CC1(C)[O:7][C:6](=[O:8])[CH:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[C:4](=[O:20])[O:3]1>C(O)(C(F)(F)F)=O.O>[F:17][C:16]([F:18])([F:19])[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH:5]([C:6]([OH:8])=[O:7])[C:4]([OH:20])=[O:3])=[CH:11][CH:12]=1
Reactant: CC1(C)OC(=O)C(Cc2ccc(C(F)(F)F)cc2)C(=O)O1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)O
Reaction time: 0.67 h

Procedure:
To a 2 L flask containing 2,2-dimethyl-5-(4-(trifluoromethyl)benzyl)-1,3-dioxane-4,6-dione (65 g, 215 mmol, Intermediate 47: step a) was added a TFA/water solution (v/v, 560 mL/280 mL) at room temperature and the white suspension was heated between 70° C. and 78° C. in a large oil bath. The suspension did not dissolve until a temperature of 72° C. was reached. After approximately 40 minutes, the suspension became a clear homogeneous solution. After 3 hours, HPLC indicated that the reaction was complete. The mixture was concentrated on the rotary evaporator and azeotroped with toluene (4×100 mL) to give white solid which was used without further purification.
Reaction SMILES: COC[O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([CH2:11][O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6]1.C(=O)=O.[CH3:24][C:25]([CH3:27])=O.C([N-]C(C)C)(C)C.[Li+].C(I)CC.[Cl-].[NH4+]>O1CCCC1.CCCCCC.O1CCCC1>[OH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([CH2:11][O:12][CH:13]([CH2:24][CH2:25][CH3:27])[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:6]1
Reactant: CC(C)=O
Reactant: COCO[C@@H]1CCC[C@H](COCC(=O)OC(C)(C)C)C1
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCI
Solvent: CCCCCC
Product: CCCC(OC[C@H]1CCC[C@@H](O)C1)C(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
200 mg of tert-butyl (cis-3-methoxymethoxycyclohexylmethoxy)acetate are dissolved in 5 ml of abs. tetrahydrofuran and cooled to −78° C. (dry ice/acetone bath). 0.7 ml of a 2M lithium diisopropylamide solution in tetrahydrofuran/hexane is then added dropwise. The solution is initially stirred at −78° C. and then warmed to 0° C. (ice bath) and stirred at this temperature for 20 min. 600 mg of propyl iodide in 2 ml of tetrahydrofuran are then added, and the solution is stirred at 0° C. for a further 2.5 h. 15 ml of a saturated ammonium chloride solution are added, and the phases are separated. The aqueous phase is extracted with methyl tert-butyl ether. The combined organic phases are dried over MgSO4 and concentrated (yield: 240 mg of crude product). The residue is taken up in 2 ml of tetrahydrofuran, 0.5 ml of conc. HCl is added and the mixture is stirred at room temperature for 18 h. The mixture is diluted with water and methyl tert-butyl ether, the phases are separated and the aqueous phase is extracted with methyl tert-butyl ether. The combined organic phases are washed with saturated NaCl solution, dried over MgSO4 and concentrated. This gives 130 mg of tert-butyl 2-(cis-3-hydroxycyclohexylmethoxy)-pentanoate as a yellow oil. NMR (CDCl3) diastereomer mixture: 3.55-3.67 (m, 2H), 3.41-3.48 (m, 1H), 3.07-3.18 (m, 1H), 1.91-2.13 (m, 2H), 1.11-1.82 (m, 14H), 1.48 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)[CH:2]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[S:22]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=1)(=[O:24])=[O:23]
Reactant: Nc1nc(-c2cccnc2)cs1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Product: O=S(=O)(Nc1nc(-c2cccnc2)cs1)c1c(Cl)cc(Cl)cc1Cl

Procedure:
The title compound was prepared from 4-(3-pyridyl)-1,3-thiazol-2-amine and 2,4,6-trichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (29.3 mg) with purity >90%: MS (pos) m/z 422.1; HRMS m/z 418.9134 (calc. of monoisotopic mass for C14H8Cl3N3O2S2 gives 418.9123).
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:7]=[C:8](/[CH:12]=[CH:13]/[CH2:14][N:15]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[C:23]([C:34](=[O:36])[NH2:35])[CH:22]=2)[S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH:9]=[CH:10][CH:11]=1)(=[NH:5])[NH2:4].CO[C:39]1[CH2:40][CH2:41][CH2:42][N:43]=1.N1CCCC1=O.Cl>C(O)C.O.C(N(CC)CC)C>[ClH:1].[ClH:1].[C:3]([C:6]1[CH:7]=[C:8](/[CH:12]=[CH:13]/[CH2:14][N:15]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]3[CH2:33][CH2:32][N:31]([C:39]4[CH2:40][CH2:41][CH2:42][N:43]=4)[CH2:30][CH2:29]3)=[C:23]([C:34](=[O:36])[NH2:35])[CH:22]=2)[S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH:9]=[CH:10][CH:11]=1)(=[NH:4])[NH2:5]
Reactant: COC1=NCCC1
Reactant: CCS(=O)(=O)N(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCNCC2)c(C(N)=O)c1
Agent: Cl
Agent: O=C1CCCN1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CCS(=O)(=O)N(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCN(C3=NCCC3)CC2)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 147 %

Procedure:
To a solution of N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[3-carbamoyl-4-(piperidin-4-yloxy)phenyl]ethanesulfonamide dihydrochloride (0.68 g) obtained in example 100(a) in ethanol (15 ml) were added successively 5-methoxy-3,4-dihydro-2H-pyrrole (0.36 g), which was prepared from 2-pyrrolidinone according to the method described in Org. Prep. Proced. Int., 24, 147 (1992), and triethylamine (0.85 ml) at room temperature and the resulting mixture was allowed to stand at room temperature overnight. At the end of this time, to the reaction mixture were furthermore added successively 5-methoxy-3,4-dihydro-2H-pyrrole (0.19 g) and triethylamine (0.34 ml) at room temperature, and the resulting mixture was stirred at room temperature for 5 hours and then evaporated in vacuo. Subsequently, to the residue obtained were successively added ethanol (10 ml) and a 4N solution of hydrogen chloride in dioxane (4 ml), and the resulting mixture was evaporated in vacuo. The residue obtained was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: 10% acetonitrile/water). To the amorphous solid obtained was added 1N hydrochloric acid (8 ml) and the resulting mixture was evaporated to dryness in vacuo. The residue obtained was dissolved in water and then lyophilized to afford the title compound (0.56 g, yield: 73%) as a pale brown amorphous solid.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4]O.O=S(Cl)[Cl:14]>C(Cl)Cl>[Cl:14][CH2:4][CH2:3][N:2]([CH3:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(CCO)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(CCCl)c1ccccc1
Temperature: 25 °C
Yield: 38.6 %

Procedure:
In a mixture of compound 2a (1.25 g, 8.3 mmol) and CH2Cl2 (50 mL), SOCl2 (1.2 mls, 16.5 mmol) was added dropwise over 20 min. During addition the solution turned from colorless to yellow. After the addition was complete, the mixture was heated to reflux for one hour. After cooling to room temperature, the mixture was quenched carefully with cold, saturated aqueous K2CO3 (50 mL). The mixture was then extracted with CH2Cl2, and the combined organic layer was washed with brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/EtOAc to provide the compound 2b (0.55 g, 3.2 mmol, 39.3% yield) as a yellow oil. HRMS (ESI, positive) m/z calcd. for C9H13ClN [M+H]+: 170.07310, found: 170.07309. 1H NMR (400 MHz, Chloroform-d) δ 7.24 (dd, J=8.8, 7.3 Hz, 2H), 6.73 (m, J=14.2, 7.6 Hz, 3H), 3.71-3.56 (m, 4H), 3.00 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].C1C(=O)N([Br:19])C(=O)C1.O>CC(O)=O>[Br:19][C:3]1[C:2]([Cl:1])=[CH:8][C:6]([NH2:7])=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(Cl)c(Br)cc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (6.0 g, 34.88 mmol) and NBS (6.06 g, 34.0 mmol) in HOAc (240 mL) was stirred at 130° C. for 1 h. The reaction mixture was poured into water. The precipitate was collected by filtration and washed with petroleum ether to give 4-bromo-5-chloro-2-nitroaniline as a light brown solid (8.25 g, 96.5%). 1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.62 (br s, 2H), 7.29 (s, 1H). LCMS (ESI) m/z 251 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:12]=2)[CH2:4][C@H:3]1[O:18][CH3:19].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[S:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:12]=3)[CH2:4][C@H:3]2[O:18][CH3:19])=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: CCOC(=O)c1cnc(N2CC[C@H](N)[C@H](OC)C2)s1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCOC(=O)c1cnc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)s1
Yield: 71 %

Procedure:
The same operation as in Example (1g) was performed using ethyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylate obtained by the method described in Example (5d) (0.22 g, 0.77 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (85 mg, 0.49 mmol), WSC hydrochloride (0.56 g, 2.92 mmol) and DMAP (0.13 g, 1.02 mmol), to obtain 0.15 g of the title compound as a pale yellow solid (71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].CC1(C)N([Br:22])C(=O)N(Br)C1=O>>[Br:22][C:8]1[C:4]([C:5]([OH:7])=[O:6])=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][CH:9]=1
Reactant: COc1cccc(C(=O)O)c1OC
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Product: COc1ccc(Br)c(C(=O)O)c1OC
Reaction time: 22 h

Procedure:
Using the procedure described herein above in Example 1, Method E, 2,3-dimethoxybenzoic acid was brominated with DBDMH to provide the following results (assay yields) after reacting for 22 hours at 20°-25° C:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[C:13]3[C:9]([CH:10]=[N:11][NH:12]3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26](Cl)=[N:27][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([N:11]2[CH:10]=[C:9]3[C:13]([CH:14]=[C:6]([O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH:7]=[CH:8]3)=[N:12]2)=[N:27][CH:28]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Clc1ccc(OCc2ccccc2)cn1
Reactant: c1cc2cn[nH]c2cc1OCC1CC1
Product: c1ccc(COc2ccc(-n3cc4ccc(OCC5CC5)cc4n3)nc2)cc1

Procedure:
Using 6-(cyclopropylmethoxy)-1H-indazole and 5-(benzyloxy)-2-chloropyridine, and in the same manner as in Example 13, step B, the title compound was obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][N:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH2:6][CH2:5][C:4]2[N:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:3]1=2.C([O-])([O-])=O.[K+].[K+].Cl[C:27](C(O[Na])=O)([F:29])[F:28].C([O-])(O)=O.[Na+]>CCOC(C)=O.CN(C=O)C>[F:28][CH:27]([F:29])[O:19][C:16]1[CH:17]=[CH:18][C:3]2[CH:2]([CH3:1])[CH2:8][N:7]([C:9](=[O:14])[C:10]([F:13])([F:11])[F:12])[CH2:6][CH2:5][C:4]=2[N:15]=1
Reactant: O=C(O[Na])C(F)(F)Cl
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2nc(O)ccc21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CN(C(=O)C(F)(F)F)CCc2nc(OC(F)F)ccc21
Temperature: 90 °C
Yield: 53.8 %

Procedure:
To a mixture of 5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (77.0 mg, 281 μmol), K2CO3 (19.0 mg, 141 μmol) and DMF (1.4 ml) was added F2ClCCO2Na (47.0 mg, 310 μmol). The mixture was heated at 90° C. for 2 h. The reaction mixture was parted between sat. aq. NaHCO3 and EtOAc. The organic layer was dried, concentrated in vacuo and purified by means of column chromatography to give 49.0 mg (54%) of 2-(difluoromethoxy)-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. MS (ESI) m/z 325.2. A mixture of 2-(difluoromethoxy)-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (28.0 mg, 86.0 μmol), K2CO3 (30 mg), MeOH (1 ml) and H2O (200 μl) was heated to reflux for 10 min. The reaction mixture was concentrated in vacuo and the resulting residue was purified by column chromatography to yield 7.0 mg (36%) of 2-(difluoromethoxy)-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 7.46 (d, 1H), 6.66 (d, 1H), 3.09 (m, 2H), 3.40-2.90 (m, 4H), 2.74, (dd, 1H), 1.31 (d, 3H) ppm.
Reaction SMILES: [Li+:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:16]C1COCCO1)([C:13]([OH:15])=[O:14])[C:10]([O-:12])=[O:11]>CO.CO.O>[Li+:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:16])([C:10]([OH:12])=[O:11])[C:13]([O-:15])=[O:14]
Reactant: O=C([O-])C(Cc1ccccn1)(OC1COCCO1)C(=O)O
Agent: [Li+]
Solvent: O
Solvent: CO
Product: O=C([O-])C(O)(Cc1ccccn1)C(=O)O

Procedure:
A solution of 0.69 g of said compound in 12 ml of MeOH is hydrolysed at r.t. with 9.3 ml of the LiOH in MeOH-H2O solution, to give 0.4 g of 3-(pyrid-2-yl)-2-hydroxy-2-carboxypropanoic acid lithium salt, m.p. >300° C., I.R (nujol) 3400, 1640 cm-1HNMR (D2O) δ (TMS): 3.4 S, 7.2-7.35 m, 7.65-7.8 m, 6.3-8.4 m.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:16][CH:17]([N:19]([CH:24]([CH3:26])[CH3:25])[C:20](=[O:23])[CH2:21]Br)[CH3:18]>>[CH:17]([N:19]([CH:24]([CH3:26])[CH3:25])[C:20](=[O:23])[CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)([CH3:18])[CH3:16]
Reactant: CC(C)N(C(=O)CBr)C(C)C
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Product: CC(C)N(C(=O)COc1ccc(-c2ccc(C#N)cc2)cc1)C(C)C
Yield: 89.3 %

Procedure:
The product was prepared as in Example 2, Stage A starting with 780 mg of 4'-hydroxy-(4-biphenyl carbonitrile) (Aldrich) and 1.33 g of N,N-bis(1-methylethyl)-2-bromo-acetamide (Preparation 8) to obtain 1.2 g of the expected product.
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:23])[N:5]([CH3:22])[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[N:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[C:4](=[O:23])[N:5]([CH3:22])[C:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)=[N:7][CH:8]=1
Reactant: COc1cnc(-c2ccc(Oc3ccccc3)cc2)n(C)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1c(-c2ccc(Oc3ccccc3)cc2)ncc(O)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a solution of 133 g (4.30 mmol) 5-methoxy-3-methyl-2-(4-phenoxyphenyl)pyrimidin-4(3H)-one in 25 ml CH2Cl2 was added 34.4 ml (34.4 mmol) of a 1 M solution of BBr3 in CH2Cl2. The reaction mixture was stirred for 1 h, cooled to 0° C., quenched with 100 ml MeOH, and concentrated in vacuo. Purification by HPLC gave 945 mg (70% yield) of 5-hydroxy-3-methyl-2-(4-phenoxyphenyl)pyrimidin-4(3H)-one. LCMS [M+H]+=2951.
Reaction SMILES: CN(C)CCNC(C1C=CC=C2C=1NC1C=CC3C=C(NS(C4C=CC(C)=CC=4)(=O)=O)C=CC=3C2=1)=O.[H-].[Na+].[Cl:39]C(OCC)=O.[CH3:45][N:46]([CH3:87])[CH2:47][CH2:48][N:49]1[C:84](=[O:85])[C:53]2[CH:54]=[CH:55][CH:56]=[C:57]3[C:58]4[C:59]5[CH:67]=[CH:66][C:65]([N:68](C(OCC)=O)[S:69]([C:72]6[CH:77]=[CH:76][C:75]([CH3:78])=[CH:74][CH:73]=6)(=[O:71])=[O:70])=[CH:64][C:60]=5[CH:61]=[CH:62][C:63]=4[N:51]([C:52]=23)[C:50]1=[O:86].[OH-].[Na+].Cl>CN(C)C=O.CO.O1CCCC1>[ClH:39].[CH3:87][N:46]([CH3:45])[CH2:47][CH2:48][N:49]1[C:84](=[O:85])[C:53]2[CH:54]=[CH:55][CH:56]=[C:57]3[C:58]4[C:59]5[CH:67]=[CH:66][C:65]([NH:68][S:69]([C:72]6[CH:73]=[CH:74][C:75]([CH3:78])=[CH:76][CH:77]=6)(=[O:71])=[O:70])=[CH:64][C:60]=5[CH:61]=[CH:62][C:63]=4[N:51]([C:52]=23)[C:50]1=[O:86]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)N(c1ccc2c(ccc3c2c2cccc4c(=O)n(CCN(C)C)c(=O)n3c42)c1)S(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)Nc2ccc3c(ccc4[nH]c5c(C(=O)NCCN(C)C)cccc5c43)c2)cc1
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Nc2ccc3c(ccc4c3c3cccc5c(=O)n(CCN(C)C)c(=O)n4c53)c2)cc1

Procedure:
The compound of Production Example 24 was treated in the same manner as the one of Production Example 3 to thereby give N-[2-(dimethylamino)ethyl]-3-(4-methylbenzenesulfonamido)-7H-benzo[c]carbazole-8-carboxamide. Then this product was reacted with sodium hydride and ethyl chloroformate in dimethylformamide under ice-cooling to thereby give 5-[2-(dimethylamino)ethyl]-11-(N-etoxycarbonyl-4-methylbenzenesulfonamido)-4H-benzo[c]pyrimido[5,6,1-jk]carbazole-4,6(5H)-dione. Next, this product was treated with a 1 N aqueous solution of sodium hydroxide in a mixture of methanol with tetrahydrofuran (1:1) and then converted into the hydrochloride in a conventional manner followed by recrystallization from ethanol to thereby give the title compound.
Reaction SMILES: CN(C)[S:3]([C:6]1[C:7](Cl)=[N:8][CH:9]=CC=1)(=O)=O.[CH2:14]1[C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH2:17][NH:16][CH2:15]1.[Na].C(O)(C(F)(F)F)=O>C1COCC1.O>[S:3]1[CH:6]=[CH:7][N:8]=[C:9]1[N:16]1[CH2:15][CH:14]=[C:19]([C:20]([OH:22])=[O:21])[CH2:18][CH2:17]1
Reactant: CN(C)S(=O)(=O)c1cccnc1Cl
Reactant: O=C(O)C1=CCNCC1
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1=CCN(c2nccs2)CC1

Procedure:
A solution of 2-chloro-pyridine-3-sulfonic acid dimethylamide (1.18 mmol) and isoguvacine, sodium salt (2.19 mmol) in THF (0.5 mL) and water (2 mL) was stirred at 90° C. for 22 hours, acidified (pH˜1) with TFA, and extracted with CH2Cl2. The organic layer was dried (Na2SO4), concentrated, and purified by flash chromatography (5% MeOH/CH2Cl2) and trituration (Et2O) to provide as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.47 (dd, J=1.7, 4.8 Hz, 1H), 8.22 (dd, J=1.7, 7.8 Hz, 1H), 7.22 (dd, J=4.8, 7.8 Hz, 1H), 7.03 (sept, J=1.7 Hz, 1H), 3.99 (q, J=3.0 Hz, 2H), 3.40 (t, J=5.6 Hz, 2H), 2.73 (s, 6H), 2.56 (m, 2 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C(O)(=O)C.[C:24](=O)([O:28]CC)[O:25][CH2:26][CH3:27]>>[CH2:26]([O:25][C:24](=[O:28])[CH2:16][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)=[O:17])[CH3:27]
Reactant: CC(=O)c1cccc(OCc2ccccc2)c1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)c1cccc(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
1-(3-Benzyloxyphenyl)ethanone (218 g, 966.10 mmol) was dissolved in diethyl carbonate and sodium hydride (60% oil) (46.37 g, 1.15 mmol) was slowly added thereto at 0° C., and then stirred for 3 hours at 60° C. After the reaction was completed, ice water and acetic acid were added to the reaction mixture, extracted with ethyl acetate/saturated sodium chloride, the organic layer was separated, and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure and the resulting residue was purified by column chromatography (ethyl acetate:hexane=1:10) to obtain 3-(3-benzyloxyphenyl)-3-oxopropionate ethyl ester (184.68 g, yield 84%) in an oil state.