Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[Na+].[Cl:7][C:8]1[N:13]=[C:12]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[C:11]([Cl:23])=[CH:10][N:9]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[C:24]1([S:30]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([C:12]3[C:11]([Cl:23])=[CH:10][N:9]=[C:8]([Cl:7])[N:13]=3)=[CH:15]2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(-c2nc(Cl)ncc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
Sodium tert-butoxide (529 mg, 5.50 mmol) was added portionwise over a period of 2 minutes to a mixture of 3-(2,5-dichloro-pyrimidin-4-yl)-1H-indole (Intermediate 11, 1.321 g, 5.0 mmol) and benzenesulfonyl chloride (0.645 mL, 5.00 mmol) in DMF (30 mL) at r.t. under N2. The resulting solution was stirred at r.t. for 1 h. Further benzenesulfonyl chloride (0.064 mL, 0.50 mmol) and sodium tert-butoxide (0.053 g, 0.055 mmol) were added and the mixture was stirred at r.t. for a further 0.25 h. The reaction was quenched by the addition of CH3OH (6 mL) and neutralised by the addition of solid CO2 pellets until reaching pH=7. The solvent was then removed in vacuo and the resulting residue was dissolved in CH2Cl2 (100 mL). This solution was filtered through a 20 g silica pad, and the eluted solution was diluted with isohexane (50 mL). This solution was concentrated in vacuo to give a volume of 70 mL and was then cooled. A resulting crystalline precipitate was collected by filtration, washed with isohexane/CH2Cl2 (4:1, 50 mL) and dried by suction to give the title compound (923 mg, 46%) as an off-white crystalline solid, which was used without further purification; 1H NMR: 7.39-7.53 (2H, m), 7.64 (2H, t), 7.75 (1H, t), 8.04 (1H, d), 8.11-8.17 (2H, m), 8.28 (1H, d), 8.79 (1H, s), 9.00 (1H, s); m/z: ES+ MH+ 404.
Reaction SMILES: C(OC([NH:11][C:12]1([C:15]2[C:16]([F:35])=[CH:17][C:18]3[C:28](=[O:29])[C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][N:20]4[C@@H:21]([CH3:25])[CH2:22][O:23][C:24]=2[C:19]=34)[CH2:14][CH2:13]1)=O)C1C=CC=CC=1.[H][H].C(Cl)Cl.C(=O)([O-])O.[Na+]>C(O)(=O)C.[C].[Pd].O>[NH2:11][C:12]1([C:15]2[C:16]([F:35])=[CH:17][C:18]3[C:28](=[O:29])[C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][N:20]4[C@@H:21]([CH3:25])[CH2:22][O:23][C:24]=2[C:19]=34)[CH2:13][CH2:14]1
Reactant: CCOC(=O)c1cn2c3c(c(C4(NC(=O)OCc5ccccc5)CC4)c(F)cc3c1=O)OC[C@@H]2C
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cn2c3c(c(C4(N)CC4)c(F)cc3c1=O)OC[C@@H]2C
Yield: 89.2 %

Procedure:
In 100 ml of acetic acid was dissolved 10 g of ethyl (S)-10-(1-benzyloxycarbonylaminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate. To the resulting solution was added 2 g of 5% palladium-carbon. The resulting mixture was stirred at room temperature for 2 hours at atmospheric pressure in a hydrogen stream. The reaction mixture was filtered. The filtrate was concentrated to dryness under reduced pressure. To the residue obtained were added 200 ml of methylene chloride and 200 ml of water in this order. The resulting mixture was adjusted to pH 7.7 with a saturated aqueous sodium hydrogen-carbonate solution. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. Diethyl ether was added to the residue obtained. The resulting crystals were collected by filtration to obtain 6.43 g (yield: 89.2%) of ethyl (S)-10-(1-aminocyclopropyl)-9-fluoro-3-methyl- 7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)=S.C1([N:39]=[C:40]=[N:41]C2CCCCC2)CCCCC1.C(N(C(C)C)CC)(C)C.N#CN>C(Cl)Cl.C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)=[N:41][C:40]#[N:39]
Reactant: COc1cc2nccc(Oc3ccc(NC(=S)Nc4ccccc4C)cc3)c2cc1OC
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N#CN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NC(=NC#N)Nc4ccccc4C)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
N-(2-Methylphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}thiourea (24 mg) obtained in Example 170, dicyclohexylcarbodiimide (45 mg) and a catalytic amount of diisopropylethyl amine were dissolved in methylene chloride (7 ml), to which a solution of cyanamide (28 mg) in THF (1 ml) was added, and the admixture was stirred at room temperature overnight. After removing the solvent by distillation, the resulting residue was purified by column chromatography on silica gel eluting with chloroform/methanol (100/1) to obtain 18 mg of the title compound (yield: 76%).
Reaction SMILES: O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:12][C:13]1[C:14]([CH3:25])=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([C:22](O)=[O:23])=[CH:16]2>O>[Cl:12][C:13]1[C:14]([CH3:25])=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH2:22][OH:23])=[CH:16]2
Reactant: Cc1c(Cl)ccc2[nH]c(C(=O)O)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cl)ccc2[nH]c(CO)cc12
Temperature: 25 °C

Procedure:
240 ml. anhydrous tetrahydrofuran and 3.5 g. lithium aluminium hydride were placed in a 1 liter three-necked flask equipped with a stirrer, dropping funnel and reflux condenser provided with a calcium chloride tube. A solution of 6.5 g. 5-chloro-4-methyl-indole-2-carboxylic acid in 100 ml. anhydrous tetrahydrofuran was then slowly added thereto dropwise, while stirring at ambient temperature, whereafter the reaction mixture was heated to 50° C. for 2 hours. After cooling, 4.7 ml. water were added very slowly and carefully thereto dropwise and precipitated inorganic compounds were filtered off with suction and then thoroughly washed with tetrahydrofuran. The combined solutions were evaporated and the oily residue was dissolved in a little diethyl ether, mixed with ligroin and, after rubbing with a glass rod, brought to crystallization. There were thus obtained 3.6 g. (59% of theory) 5-chloro-4-methyl-2-hydroxymethyl -indole which can be recrystallized from toluene, with the use of active charcoal. The product had a melting point of 108° C.
Reaction SMILES: Br[C:2]1[CH:3]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=1.C1CCN2C(=NCCC2)CC1.CCCCCC.CCOC(C)=O>CS(C)=O>[CH:3]1([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[C:2]1
Reactant: OCCCCCCOC1CCCCCC=C1Br
Agent: OCCCCCCOC1CCCCC/C=C\1Br
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: OCCCCCCOC1C#CCCCCC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a magnetically stirred solution of 6-{[(2E)-2-bromocyclooct-2-en-1-yl]oxy}hexan-1-ol 200 mg (0.658 mmol 1 eq) in dry DMSO (3.5 ml) under Ar atmosphere, DBU (6.58 mmol, 10 eq, 1 ml) were added. The reaction was warmed to 60° C. and was stirred at this temperature for 16 h. Reaction was controlled until complete disappearance of the starting material by TLC (Hexane/AcOEt 7/3 as eluent). The reaction was quenched with a saturated solution of NH4Cl, layers were separated and the aqueous layer was extracted with Et2O (3×20 ml). Combined organic layer was washed with Brine (20 ml), dried over Na2SO4 filtered and concentrated under vacuum. Raw material was purified by chromatography on silica gel column (55 g) (Hexane:AcOEt 7/3) to obtain 6-(cyclooct-2-yn-1-yloxy)hexan-1-ol.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2[C:9]([F:15])=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.BrC1C([F:23])=CC=CN=1.FC1C([N+]([O-])=O)=CC=CC=1B(O)O>>[F:15][C:9]1[C:8]([C:3]2[C:2]([F:23])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:14]
Reactant: Nc1cccc(-c2ncccc2Cl)c1F
Reactant: Fc1cccnc1Br
Agent: O=[N+]([O-])c1cccc(B(O)O)c1F
Product: Nc1cccc(-c2ncccc2F)c1F

Procedure:
was prepared by using the same procedures as described for the preparation of 3-(3-chloro-pyridin-2-yl)-2-fluoro-phenylamine in Scheme C6, starting from 2-bromo-3-fluoropyridine [40273-45-8] and 2-fluoro-3-nitrophenylboronic acid [1150114-29-6]. MS (LC-MS): 207 [M+H]+; tR (HPLC conditions k): 2.39 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]([Cl:27])[N:18]=[C:17]([Cl:28])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.Cl.O1CCOCC1>[ClH:27].[ClH:27].[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:20]1[C:19]([Cl:27])=[N:18][C:17]([Cl:28])=[N:16][C:15]=1[NH:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH3:26]
Reactant: CCOC(=O)Cc1c(Cl)nc(Cl)nc1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)Cc1c(Cl)nc(Cl)nc1NC1CCNCC1

Procedure:
A solution of 4-(2,6-dichloro-5-ethoxycarbonylmethyl-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.87 g, 2.01 mmol) in dichloromethane (10 mL) and 4 M HCl in dioxane (40 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 333.1 [M+H]+.
Reaction SMILES: C1([O:6][C:7](=[O:43])[CH:8]([O:37][CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH:19]3[CH2:23][N:22]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)[C:21](=[O:35])[N:20]3[CH3:36])=[CH:12][CH:11]=2)CCCC1.[OH-].[Na+]>C(O)C>[CH:38]1([O:37][CH:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH:19]3[CH2:23][N:22]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=4)[C:21](=[O:35])[N:20]3[CH3:36])=[CH:12][CH:11]=2)[C:7]([OH:43])=[O:6])[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCOc1ccc(CC(OC2CCCC2)C(=O)OC2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCOc1ccc(CC(OC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2-cyclopentyloxy-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid cyclopentyl ester (0.108 g, 0.179 mmol) in ethanol (10 mL) was treated with aqueous 5 N NaOH (1 mL) and stirred at room temperature for 3 h. The solvent removed in vacuo. The resultant residue was acidified with aqueous 1 N HCl (10 mL) and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford 0.106 g of crude acid that was purified by chiral HPLC (20×250 nm Chiralpak AD, 3:2 heptane:IPA with 0.1% trifluoroacetic acid mobile phase, 14 mL/min, 225 nm) to give 0.080 g (83%) of 100% de 2-cyclopentyloxy-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid. 1H NMR. HRMS (ES+) m/z exact mass calc'd for C28H34N2O5F3 (M+1) 535.2420. Found m/z 535.2408.
Reaction SMILES: [Br:1][CH:2]=[C:3](Br)[CH:4]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].N12CCCC1=NCCC2.CS(C)=O>O>[Br:1]/[CH:2]=[CH:3]/[CH:4]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC(OC1CCCCO1)C(Br)=CBr
Agent: C1CN=C2CCCN2C1
Solvent: CS(C)=O
Solvent: O
Product: CCCCCC(/C=C/Br)OC1CCCCO1

Procedure:
A mixture of 3.7 parts of 1,2-dibromo-3(RS)-(tetrahydropyran-2-yl)oxy-1-octene, 1.25 parts of 1,5-diazabicyclo[4.3.0]non-5-ene and 25 parts by volume of dimethyl sulfoxide is warmed at 80° for 1 hour, then cooled, diluted with water and extracted with ether. The ethereal extract is washed with water, dried over anhydrous sodium sulfate and stripped of solvent. The material which remains is chromatographed on silica gel to yield 1-bromo-3(RS)-(tetrahydropyran-2-yl)oxy-trans-1-octene, which is employed in the same manner as the iodooctene compound in Example 25 to produce the organo-copper compound, 3(RS)-(tetrahydropyran-2-yl)oxy-1-octenyl copper. That material is employed in situ as described in Example 25 to afford the products of Example 25.
Reaction SMILES: C(O)(=O)C1C(=CC=CC=1)S.ClC1C=CC(S[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[N:21]([CH2:33][C:34]([OH:36])=[O:35])[C:20]=2[CH3:37])=CC=1>C(O)(C(F)(F)F)=O>[CH3:37][C:20]1[N:21]([CH2:33][C:34]([OH:36])=[O:35])[C:22]2[C:27]([CH:19]=1)=[C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:24][CH:23]=2
Reactant: Cc1c(Sc2ccc(Cl)cc2)c2c(NS(C)(=O)=O)cccc2n1CC(=O)O
Agent: O=C(O)c1ccccc1S
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(NS(C)(=O)=O)cccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thiosalicylic acid (0.35 g) was added to a solution of the product from Example 2 part (i) (0.47 g) in TFA (10 ml). The mixture was stirred at room temperature for 1 hour and then heated at 60° C. for 4 hours. The TFA was evaporated and the residue dissolved in EtOAc. The organics were washed with aqueous sodium bicarbonate and brine, died (MgSO4) and evaporated. The residue was purified using chromatography (50% EtOAc/hexane as eluent) to give the sub-title compound (0.16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:23]([CH3:27])([CH3:26])[C:24]#[N:25].C([NH:31]C1C=CC(S(N=[N+]=[N-])(=O)=O)=CC=1)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:15][C:14](=[O:16])[C:13](=[NH:31])[C:12](=[O:17])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:23]([CH3:27])([CH3:26])[C:24]#[N:25]
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)C(=N)C(=O)O2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-{2-chloro-4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propionitrile (0.5 g, 1.29 mmol) from step 5 of example B(22), and p-acetamidobenzenesulfonyl azide (0.46 g, 1.94 mmol) in THF (4 mL) under argon was added TEA (0.54 mL, 3.87 mmol). The resulting solution was stirred at 25° C. overnight. The solvents were removed and the residue was purified by flash column chromatography (25–60% % EtOAc in hexanes) to give the product as a yellow oil. ESIMS (MH+): 414.
Reaction SMILES: [Sn](Cl)Cl.Cl.[I:5][C:6]1[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=1[O:8][CH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[C:11]=1[C:12]#[N:13].[OH-].[K+]>>[NH2:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:10]([CH2:9][O:8][C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=2[I:5])[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(COc2ccccc2I)cccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Product: N#Cc1c(N)cccc1COc1ccccc1I
Temperature: 15 °C
Reaction time: 3 h
Yield: 34.6 %

Procedure:
To a cooled (15° C.) and stirred solution of tin (II) chloride (0.74 g, 3.29 mmol) and con. hydrochloric acid (2.0 mL) was added a solution of 2-(2-iodophenoxymethyl)-6-nitrobenzonitrile (250.0 mg, 0.66 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was poured on to crushed-ice and potassium hydroxide solution, stirred, extracted with dichloromethane, filtered and dried. Purification by silica gel chromatography (dichloromethane) yielded 80 mg of 2-amino-6-(2-iodophenoxymethyl)benzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:15]3[CH:16]=[C:17]([O:24][CH3:25])[C:18]([O:20]C(=O)C)=[CH:19][C:14]=3[CH:13]([CH2:26][CH3:27])[C:12]([CH3:28])=[N:11][N:10]=2)=[CH:5][C:4]=1[O:29]C(=O)C.[OH-].[K+].[Cl-].[Na+].[Cl-].[NH4+]>O.C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:15]3[CH:16]=[C:17]([O:24][CH3:25])[C:18]([OH:20])=[CH:19][C:14]=3[CH:13]([CH2:26][CH3:27])[C:12]([CH3:28])=[N:11][N:10]=2)=[CH:5][C:4]=1[OH:29]
Reactant: CCC1C(C)=NN=C(c2ccc(OC)c(OC(C)=O)c2)c2cc(OC)c(OC(C)=O)cc21
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCC1C(C)=NN=C(c2ccc(OC)c(O)c2)c2cc(OC)c(O)cc21
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
A mixture of 0.44 g of 1-(4-methoxy-3-acetoxyphenyl)-4-methyl-5-ethyl-7-acetoxy-8-methoxy-5H-2,3-benzodiazepine, 8 ml of ethanol, 8 ml of water and 0.4 g of potassium hydroxide is stirred in nitrogen atmosphere for 15 minutes. 50 ml of 20% aqueous sodium chloride solution and 0.6 g of ammonium chloride are added to the solution. The precipitate is separated and recrystallized from 7.5 ml of 20% aqueous dimethyl formamide. 0.23 g of pure 1-(4-methoxy-3-hydroxyphenyl)-4-methyl-5-ethyl-7-hydroxy-8-methoxy-5H-2,3-benzodiazepine are obtained; the product decomposes at 210°-212° C. This compound is identical with the product obtained according to Example 26, and no depression of melting point can be observed when admixing the two products with each other.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[C:16]1([CH2:22][C:23](=[O:27])[C:24](O)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:8]([O:7][C:3]([O:4][CH2:5][CH3:6])([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:2][NH:1][C:24](=[O:25])[C:23]([CH2:22][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:27])[CH3:9]
Reactant: CCOC(CN)(OCC)c1cccnc1
Reactant: O=C(O)C(=O)Cc1ccccc1
Product: CCOC(CNC(=O)C(=O)Cc1ccccc1)(OCC)c1cccnc1

Procedure:
In a manner analogous to Example 1, by condensing 3-(2-amino-1,1-diethoxyethyl)pyridine with phenylpyruvic acid there is obtained N-[2,2-diethoxy-2-(3-pyridyl)ethyl]-3-phenylpyruvamide as an amorphous, yellow solid. Subsequent acidic hydrolysis to 3-phenyl-N-[[(3-pyridyl)carbonyl]methyl]pyruvamide and ring closure gives 3-benzyl-5-(3-pyridyl)-2(1H)-pyrazinone as a solid, melting point 188°-190° (from ethyl acetate).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].Br[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>>[CH2:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=CCCCCCOCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Product: O=[N+]([O-])c1ccc(CCCCCCCOCc2ccccc2)cc1
Yield: 68.3 %

Procedure:
General procedure M was used to convert 5.90 mmol of 11a and 6.49 mmol of 1-bromo-4-nitrobenzene to 4.03 mmol (68%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH:13]([C:15]1[C:23]2[O:22][C:21]([CH3:25])([CH3:24])[CH2:20][C:19]=2[C:18]([CH3:26])=[C:17]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:16]=1[CH3:35])=[O:14].O>C(OCC)C.C1COCC1.CCCCCC.C(OCC)(=O)C>[OH:14][CH:13]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:15]1[C:23]2[O:22][C:21]([CH3:24])([CH3:25])[CH2:20][C:19]=2[C:18]([CH3:26])=[C:17]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:16]=1[CH3:35]
Reactant: Brc1ccccn1
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(C)O2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c2c(c(C(O)c3ccccn3)c(C)c1NC(=O)CC(C)(C)C)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To a solution of 2-bromopyridine (553 mg, 3.5 mmol) in diethyl ether (3.0 mL) was added dropwise at −70° C. under argon atmosphere n-butyllithium (1.6 M, hexane solution, 2.13 mL, 3.4 mmol) and the mixture was stirred for 30 minutes. To the reaction solution was added dropwise at −70° C. a solution of N-(7-formyl-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (317 mg, 1.0 mmol) obtained in Example 340 in THF (4.0 mL) and the mixture was stirred for 30 minutes, and then warmed to room temperature. Water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:10), and then by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 270 mg (yield: 68%) of the title compound. Melting point: 176-177° C. (ethyl acetate-hexane).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([N:13]1[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][OH:25])=[N:14]1)[CH:7]=[CH:6]2.[ClH:26]>>[ClH:26].[OH:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][O:19][C:15]1[CH:16]=[C:17]([CH3:18])[N:13]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]3)[N:14]=1
Reactant: COc1ccc2cc(-n3nc(OCCNCCO)cc3C)ccc2c1
Agent: Cl
Product: Cc1cc(OCCNCCO)nn1-c1ccc2cc(O)ccc2c1
Yield: 81 %

Procedure:
A solution of 2-(2-(1-(6-methoxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethylamino)etanol (104 mg, 0.307 mmol) in HCl conc. (4 ml) was heated to reflux during 7 hrs. Then, it was cooled and evaporated to dryness in a rotavapor, the crude residue was washed with ethyl ether and 91 mg of 6-(3-(2-(2-hydroxyethylamino)ethoxy)-5-methyl-1H-pyrazol-1-yl)naphthalen-2-ol hydrochloride were obtained as a solid with a melting point=115-118° C. (yield: 81%)
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=O)[C:4]=2[CH:3]=1.[BH3-]C#[N:16].[Na+]>C(O)(C)C>[F:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([NH2:16])[C:4]=2[CH:3]=1
Reactant: [BH3-]C#N
Reactant: O=C1CCCCc2ccc(F)cc21
Agent: [Na+]
Solvent: CC(C)O
Product: NC1CCCCc2ccc(F)cc21

Procedure:
3-Fluoro-6,7,8,9-tetrahydro-benzocyclohepten-5-one (5.00 g, 28.00 mmol), NaBH3CN (12.50 g, 0.20 mol) and NH4OAc (65.00 g, 0.84 mol) in isopropanol were reacted according to the protocols as outlined in general procedure C to afford the title amine.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.ClCCCl.S(Cl)(Cl)=O.[C:19]1([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH2:32])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[NH:25][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=C(O)c1ccc(I)cc1
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: ClCCCl
Product: O=C(Nc1ccccc1Nc1ccccc1)c1ccc(I)cc1
Yield: 96.6 %

Procedure:
Suspending 5.0 g (20 mmol) of 4-iodobenzoic acid into 50 milliliter of 1,2-dichloroethane, added 3 drops of N,N-dimethylformamide. Further adding 3.6 g (30 mmol) of thionyl chloride, the resultant suspension was refluxed with heating for 2 hours. Subsequently, removing the solvent by distillation, the residue was dissolved into 50 milliliter of N-methylpyrrolidone and then, further adding 3.7 g (20 mmol) of N-phenyl-1,2-phenylenediamine, the resultant solution was stirred at room temperature for 5 hours. After completion of the reaction, adding water and filtering the precipitated solid, washing with water and further with methanole, 8.0 g of crude 4-iodo-N-(2-phenylamino-phenyl)-benzamide was obtained.