Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][CH2:11][C:12](OCC)(OCC)OCC.O>C(O)C>[Cl:10][CH2:11][C:12]1[O:9][C:3]2[CH:4]=[CH:5][C:6]([Br:8])=[CH:7][C:2]=2[N:1]=1
Reactant: CCOC(CCl)(OCC)OCC
Reactant: Nc1cc(Br)ccc1O
Solvent: O
Solvent: CCO
Product: ClCc1nc2cc(Br)ccc2o1
Temperature: 25 °C

Procedure:
2-Amino-4-bromophenol (1.6 g) prepared according to U.S. Pat. No. 4,157,444 was dissovled in ethanol (5 ml) and 2-chloro-1,1,1-triethoxyethane (1.9 g) was added. The resulting solution was warmed on a steambath for 1.5 hour. After cooling the reaction mixture to room temperature, cold water (5 ml) was added. The precipitated solid was collected and air-dried to obtian the product (1.12 g; m.p. 63°-65° C.)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:10]=2[N:11]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:9]1[C:10]2[N:11]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=c1[nH]cnc2ccc(F)nc12
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc2ncnc(Cl)c2n1
Reaction time: 2 h
Yield: 100 %

Procedure:
A suspension of 6-fluoro-3H-pyrido[3,2-d]pyrimid-4-one (0.20 g, 1.21 mmol) in POCl3 (30 mL) is heated under reflux with stirring until homogeneous (2 h), and then for a further 1 h. Excess POCl3 is removed under reduced pressure, and the residue is partitioned between CH2Cl2 and saturated aqueous NaHCO3. Workup of the organic portion gives crude 4-chloro-6-fluoropyrido[3,2-d]pyrimidine (100%) as an unstable white solid which is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](/[CH:23]=[CH:24]/[O:25]C)[C:18]=3[CH2:27][CH3:28])=[N:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:27][CH3:28])=[C:19]([CH2:23][CH:24]=[O:25])[CH:20]=[CH:21][CH:22]=3)=[N:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(/C=C/OC)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(CC=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 70 °C
Reaction time: 4 h
Yield: 100.4 %

Procedure:
To a solution of 2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-5-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3,4-thiadiazole (D14) (100 mg) in tetrahydrofuran (THF) (15 mL) stirred under nitrogen at room temperature was added 2M HCl/water (0.3 mL). The reaction mixture was stirred at 70° C. for 4 h. The reaction mixture was concentrated to afford the crude product [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]acetaldehyde (D15) (97 mg). MS (ES): C21H21ClN2O2S requires 400. found 401.1 (M+H+).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:8]2[C:9](=[O:12])[C:10]=1[OH:11])=[O:4].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>CO>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:3]([C:5]2[N:6]=[C:7]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:8]3[C:9](=[O:12])[C:10]=2[OH:11])=[O:4])=[CH:21][CH:20]=1
Reactant: COC(=O)c1nc2ccc(Br)cn2c(=O)c1O
Reactant: NCc1ccc(F)cc1
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)c1nc2ccc(Br)cn2c(=O)c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.4 %

Procedure:
7-Bromo-3-hydroxy-4-oxo-4H-pyrido[1,2-α]pyrimidine-2-carboxylic acid methyl ester (20 mg, 0.07 mmol) and p-fluorobenzylamine (19 uL, 0.17 mmol) in dry methanol (4 mL) was heated to reflux with stirring. Reaction progress was monitored by HPLC. After 6 h, the reaction was cooled to room temperature and concentrated in vacuo. The residue was triturated with diethyl ether (2 mL) and the precipitate collected by filtration and washed with diethyl ether (10 mL) and dried on the pump to afford 7-bromo-3-hydroxy-4-oxo-4H-pyrido[1,2-α]pyrimidine-2-carboxylic acid 4-fluoro-benzylamide (24 mg, 92%) as a yellow brown solid.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[CH:10]12[CH2:11][CH:12]([CH:8]=[CH:9]1)[CH:2]1[C:1]([O:6][C:4](=[O:5])[CH:3]21)=[O:7]
Reactant: O=C1C=CC(=O)O1
Reactant: C1=CCC=C1
Solvent: Cc1ccccc1
Product: O=C1OC(=O)C2C3C=CC(C3)C12
Temperature: 120 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
12.5 g of maleic anhydride and 8 g of cyclopentadiene were dissolved in 100 ml of toluene, and the mixture was heated while stirring at 120° C. for 2 hours in an autoclave. Toluene was distilled off to obtain 18 g (0.116 mol) of a 5-norbornene-2,3-dicarboxylic acid anhydride. To this was added 125 g of a 3.7 wt % sodium hydroxide aqueous solution to control the pH value to 7.1, giving a deodorant base agent 2 which was evaluated (first acid dissociation index 4.16, second acid dissociation index 6.23).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][CH:9]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.CN([CH:21]=[O:22])C>C(Cl)Cl>[CH:21]([C:9]1[NH:10][CH:11]=[CH:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=1)=[O:22]
Reactant: CN(C)C=O
Reactant: Ic1ccc(-c2cc[nH]c2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1[nH]ccc1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4 (5.15 g, 19.1 mmol) in DMF (6.1 mL) and CH2Cl2 (140 mL) under argon was cooled to 0° C. and then POCl3 (2.11 mL, 22.6 mmol) was added dropwise. After 1 h, the flask was warmed to room temperature and stirred overnight. The reaction was quenched at 0° C. with 2.5 M NaOH (100 mL). The mixture was poured into water (500 mL), extracted with CH2Cl2, and the combined organic layers were washed with water, brine, dried (Na2SO4), and the solvent was removed in vacuo. 1H NMR spectroscopy showed two regioisomers in a ˜6:1 ratio. The minor isomer exhibited signals at δ 7.21 and 7.39 ppm, compared with signals at δ 6.42 and 7.14 for the major isomer. The most downfield signal (7.39 ppm) is assigned to the proton adjacent to a formyl group, which occurs in the 2-formyl-4-aryl substituted pyrrole. Recrystallization from ethyl acetate afforded an orange solid corresponding to the major aldehyde (2.25 g). The mother liquor was concentrated and purified by flash column chromatography [silica, hexanes/ethyl acetate (3:1)]. The first fraction corresponded to the major aldehyde (1.25 g). The total yield of the title compound was 3.50 g (62%): mp 153-154° C.; 1H NMR δ 6.42 (m, 1H), 7.14 (m, 1H), 7.22 (m, 2H), 7.76 (m 2H), 9.59 (s, 1H), 10.72 (br, 1H); 13C NMR δ 93.5, 104.3, 111.4, 125.8, 128.6, 130.8, 133.1, 137.8, 179.4; FAB-MS obsd 296.9663, calcd 296.9651; Anal. Calcd for C10H8INO: C, 44.5; H, 2.7; N, 4.7. Found: C, 44.4; H, 2.7; N, 4.6.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Br:11])[CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:3]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)C>[C:21]1([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([Br:11])[CH:9]=3)[N:4]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(Br)cnc21
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=S(=O)(c1ccccc1)n1cc(-c2ccccc2)c2cc(Br)cnc21
Temperature: 110 °C

Procedure:
To a solution of 3-iodo-5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (250 mg, 0.54 mmol) in a 3:1 toluene/ethanol mixture (17 ml) are added benzene boronic acid (65 mg, 0.54 mmol), K2CO3 (1.6 ml of 2 M solution in water, 3.20 mmol) and Pd(PPh3)4 (1.5 mol %) and the reaction is heated at 110° C. for 3.5 hours under argon.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:5]=[CH:4][C:3]=1[C:18]1[N:23]=[CH:22][C:21](Br)=[CH:20][N:19]=1.C(N[CH:29]([CH3:31])[CH3:30])(C)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:5]=[CH:4][C:3]=1[C:18]1[N:23]=[CH:22][C:21]([C:7]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:31][CH2:29][CH3:30])=[CH:20][N:19]=1
Reactant: CC(C)NC(C)C
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)c(F)c1F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCC#Cc1cnc(-c2ccc(OCCCCCCCC)c(F)c2F)nc1
Yield: 92 %

Procedure:
-Non-1-yne (1.0 ml, 6.4 mmol) was added via syringe to degassed mixture of 2-(2',3'-difluoro-4'-octyloxyphenyl)-5-bromopyrimidine 4 (1.27 g, 3.18 mmol), tetrakis(triphenylphosphine)palladium (173 mg, 0.15 mmol) and copper(I) iodide (29 mg, 0.15 mmol) in diisopropylamine (60 ml) under nitrogen. The mixture was heated under gentle reflux for 4 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (5% ethyl acetate-light petroleum, the sample was preloaded onto silica in dichloromethane) to give the nonynylpyrimidine 38 (1.29 g, 92%) (from MeOH), transitions/° C. K 64.4 (N 63.3) I; νmax /cm-1 (KBr) 2920, 2850, 2220, 1615, 1520, 1470, 1430s, 1295, 1205 and 1090s; δ 0.90 (6 H, m), 1.20-1.55 (18 H, m), 1.64 (2 H, quint, J 7, CH2CH2C≡C), 1.85 (2 H, quint, J 7, OCH2CH2), 2.46 (2 H, t, J 7, CH2C≡C), 4.10 (2 H, t, J 7, OCH2), 6.83 (1H, ddd, J 8, 7 and 2, 5'-H), 7.85 (1H, ddd, J 8, 7 and 2, 6'-H_ an d8.79 (2 H, s, 4- and 6-H), m/z 442 (M+), 330, 288, 287, 274, 273, 247 and 220.
Reaction SMILES: C[O-].[Na+].[CH3:4][C@:5]12[C:13](=[O:14])[CH2:12][C@H:8]([C:9]1([CH3:11])[CH3:10])[CH2:7][CH2:6]2.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[CH:19]=O.O>C1CCCCC1>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[CH:19]=[C:12]1[CH:8]2[C:9]([CH3:10])([CH3:11])[C:5]([CH3:4])([CH2:6][CH2:7]2)[C:13]1=[O:14]
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: O
Product: COc1ccc(OC)c(C=C2C(=O)C3(C)CCC2C3(C)C)c1
Temperature: 50 °C

Procedure:
A suspension of 9.2 g (0.17 mol) of sodium methoxide in 200 ml of cyclohexane is initially introduced into an apparatus rendered inert with nitrogen and the mixture is treated with a solution of 18.2 g (0.12 mol) of DL-camphor in 100 ml of cyclohexane. The mixture is heated to 50° C. with stirring and 25 g (0.15 mol) of molten 2,5-dimethoxybenzaldehyde are then added. The reaction mixture is heated under reflux for 3 hours. After cooling, it is treated with 300 ml of water. The organic phase is separated off, washed with 1N hydrochloric acid and then with saturated sodium chloride solution, and dried over sodium sulfate. After removing cyclohexane in vacuo, 17.1 g of crude product are obtained. Excess DL-camphor is removed by steam distillation. After chromatography on silica gel 60 using toluene/ethyl acetate in the ratio 3:1 as the eluent, an oil is obtained which after some time solidifies to give 9.2 g of crystalline 3-(2',5' -dimethoxybenzylidene)camphor of melting point 70°-72° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2.[OH-].[Na+].[CH2:15]1[CH2:21][S:18](=[O:20])(=[O:19])[O:17][CH2:16]1>O.C1COCC1>[CH:10]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]([CH2:5]3)[CH:3]1[NH:2][CH2:16][CH2:15][CH2:21][S:18]([OH:20])(=[O:19])=[O:17])[CH2:9]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: O=S1(=O)CCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(O)CCCNC1C2CC3CC(C2)CC1C3
Yield: 74 %

Procedure:
The 2-aminoadamantane hydrochloride (2×5 g) was treated with NaOH in water. The aqueous mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate. The solvent was removed under reduced pressure. The resulting white solid was dried 30 minutes at room temperature under vacuum. A solution of 1,3-propane sultone (7.4 g, 60 mmol) in THF was added to a solution of the free amine (7.98 g, 52 mmol) in THF (70 mL, total). The mixture was heated under reflux for 4 h, cooled into an ice bath. The solid was collected by filtration, air-dried for 15 min, and further dried in vacuo (11.2 g). Recrystallization was done with methanol/water (60 mL/35 mL). After cooled in a fridge, the solid was collected by filtration, rinsed with methanol, dried in the vacuum oven at 60° C. overnight. A white crystalline sandy solid (small plates, 10.45 g, 74% yield) was obtained. The 1H and 13C NMR were consistent with the structure of Compound BZ.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][CH:17]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[Br:27]N1C(=O)CCC1=O>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+].O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][C:17]=3[Br:27])[CH:10]=[N:9]2)=[CH:25][CH:26]=1
Reactant: COc1ccc(Cn2cc(-c3csc(Nc4ccccn4)n3)cn2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3nc(Nc4ccccn4)sc3Br)cn2)cc1
Yield: 95.7 %

Procedure:
According to Scheme 5 Step 1: A solution of N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-2-yl)pyridin-2-amine (4.20 mmol, 1.53 g) and N-bromosuccinimide (4.40 mmol, 782 mg) in DMF (76 mL) was stirred for 1.5 hour at 50° C. The reaction mixture was diluted with a saturated solution of Na2CO3 and water. The precipitate formed was recovered and washed with DCM. The aqueous phase was extracted with DCM and the organic phase was washed. The organic phase was dried over MgSO4, was filtered and was concentrated to yield with the addition of the precipitate N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-bromothiazol-2-yl)pyridin-2-amine (4.02 mmol, 1.78 g, 96%) as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([CH2:19][S:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Sn](Cl)Cl.O>C(O)C.C(OCC)(=O)C>[NH2:27][C:23]1[CH:22]=[C:21]([S:20][CH2:19][C:12]2[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[N:14][C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:10][CH:11]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1CSc1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1CSc1cccc(N)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of N2-(3-fluorophenyl)-5-(((3-nitrophenyl)thio)methyl)-N4-propylpyrimidine-2,4-diamine (E19, 160 mg) in ethanol (4 mL) and ethyl acetate (8 mL), tin(II) chloride (739 mg) was added at room temperature, and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added to the mixture. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 5-(((3-aminophenyl)thio)methyl)-N2-(3-fluorophenyl)-N4-propylpyrimidine-2,4-diamine (E20).
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](Cl)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2C=C[C:41]([C:42]([N:44]3[C:50]4C=CC=C[C:49]=4[CH2:48][N:47]4[C:55](C(O)=O)=[CH:56][CH:57]=[C:46]4C3)=O)=CC=2)CCCCC1.N1(C2CCNCC2)CCCC1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27]([N:44]5[CH2:42][CH2:41][CH:48]([N:47]6[CH2:46][CH2:57][CH2:56][CH2:55]6)[CH2:49][CH2:50]5)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Reactant: O=C(O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Agent: C1CCN(C2CCNCC2)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2)N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of the crude 10-(4-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carbonyl chloride (prepared in the manner of Example 23, from 1 g of the corresponding carboxylic acid of Example 22) in dichloromethane (25 mL) was treated with 4-(1-pyrrolidinyl) piperidine (0.74 g), N,N-diisopropylethyl amine (0.31 g) and 4-(dimethylamino)pyridine (0.05 g). The reaction mixture was stirred at room temperature overnight, washed with water and saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. Filtration of this solution through a short column of Magnesol® gave a pale yellow eluate which was evaporated to dryness to provide the title compound as a pale yellow amorphous material (0.42 g).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni]>[N:7]1[CH:2]=[CH:3][CH:4]=[C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)[N:6]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CNc2ccc(Cl)nn2)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC(CNc2cccnn2)CC1

Procedure:
Benzyl 4-{[(6-chloro-3-pyridazinyl)amino]methyl}-1piperidinecarboxylate (EXAMPLE 22) (400 mg, 1.11 mmol) was dissolved in absolute ethanol. Raney nickel (65 mg, 1.11 mmol) was then added and the resulting reaction was stirred under 1 atm hydrogen for 18 h. The catalyst was filtered and the filtrate was concentrated under reduced pressure. The resulting clear oil was purified by silica gel chromatography to give the title compound as a clear oil.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:32](=[O:43])[CH:31]2[C:44]1[C:45]([OH:53])=[CH:46][C:47]2[O:51][CH2:50][CH2:49][C:48]=2[CH:52]=1>>[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:32](=[O:43])[C:31]2([C:44]1[C:45]([OH:53])=[CH:46][C:47]2[O:51][CH2:50][CH2:49][C:48]=2[CH:52]=1)[CH2:5][OH:16]
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)OCC3)c2cc(Cl)ccc21
Product: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)OCC3)c2cc(Cl)ccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with ethyl [5-chloro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (99%): MS (ES+) m/z 418.7 (M+1).
Reaction SMILES: [OH:1][C:2]1([C:14]([O:16]C)=[O:15])[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.O[Li].O>>[OH:1][C:2]1([C:14]([OH:16])=[O:15])[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)C1(O)CCCc2c(OC)cccc21
Agent: [Li]O
Solvent: O
Product: COc1cccc2c1CCCC2(O)C(=O)O

Procedure:
Prepared according to the method described in Example 1(ii) above from 1-hydroxy-5-methoxytetralin-1-yl-carboxylic acid, methyl ester (1.11 g; 4.7 mmol; from step (i) above) and LiOH.H2O (0.395 g; 9.4 mmol). Yield 460 mg (36%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:34])[N:19]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=[C:21]([C:23](O)=[O:24])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH2:67]([N:74]1[CH:78]=[C:77]([NH2:79])[CH:76]=[N:75]1)[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:34])[N:19]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=[C:21]([C:23](=[O:24])[NH:79][C:77]2[CH:76]=[N:75][N:74]([CH2:67][C:68]3[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=3)[CH:78]=2)[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cnn(Cc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(C(=O)O)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2cc(C(=O)Nc3cnn(Cc4ccccc4)c3)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Temperature: 90 °C

Procedure:
Intermediate (1c), 2-[5-carboxy-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylic acid tert-butyl ester (300 mg, 0.62 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (357 mg, 1.86 mmol), 1-hydroxybenzotriazole hydrate (251 mg, 1.86 mmol), N,N-diisopropylethylamine (320 mg, 0.431 mL, 2.48 mmol), 1-benzyl-1H-pyrazol-4-ylamine (322 mg, 1.86 mmol) and tetrahydrofuran (12 mL) were combined in a 20 mL microwave vial. The contents of the vial were heated at 90° C. for 30 minutes under microwave irradiation. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and dichloromethane, and the organic layer was separated. The aqueous was extracted with a further portion of dichloromethane and the combined dichloromethane layers were dried (Na2SO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting with 20% ethyl acetate/hexane and then 2% methanol/dichloromethane to afford the desired title compound as a solid, 315 mg, 80%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](/[CH:20]=[C:21]3\[O:22][C:23]4[C:30]([CH2:31][N:32]5[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]5)=[C:29]([OH:45])[CH:28]=[CH:27][C:24]=4[C:25]\3=[O:26])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](/[CH:20]=[C:21]3\[O:22][C:23]4[C:30]([CH2:31][N:32]5[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]5)=[C:29]([OH:45])[CH:28]=[CH:27][C:24]=4[C:25]\3=[O:26])=[CH:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(=O)(=O)c4ccc(Cl)cc4)c4ccccc24)C3=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C1/C(=C/c2cn(S(=O)(=O)c3ccc(Cl)cc3)c3ccccc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 179.9 %

Procedure:
A solution of tert-butyl (Z)-4-[(2-{[1-(4-chlorophenylsulfonyl)-1H-indol-3-yl]methylene}-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.153 g, 0.235 mmol) in methylene chloride (6 mL) was added with trifluoroacetic acid (6 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, then a solution of the resulting residue in methanol (8 mL) was added with a 5% solution of hydrogen chloride in methanol (2 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the resulting solid was suspended in acetonitrile and thereby washed to obtain (Z)-2-{[1-(4-chlorophenylsulfonyl)-1H-indol-3-yl]methylene}-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.0878 g, 60%).