Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][CH2:17][CH2:18]O)=[C:8]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:42])[CH2:40][CH3:41])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>>[C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][CH2:17][CH2:18][N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:42])[CH2:40][CH3:41])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)=[C:8]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCc1c(-c2ccccc2)n(-c2ccccc2)c2ccccc12
Reactant: CCC(=O)Nc1ccc(C2CCNCC2)cc1
Product: CCC(=O)Nc1ccc(C2CCN(CCCc3c(-c4ccccc4)n(-c4ccccc4)c4ccccc34)CC2)cc1

Procedure:
Prepared by Procedure O and Scheme W using 3-(1,2-diphenyl-1H-indol-3-yl)-1-propanol and N-[4-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 542.0 (M+H)+.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: NN1CCCC1
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NN2CCCC2)cn1
Yield: 17 %

Procedure:
As described for example 8d, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (200 mg, 0.66 mmol) was converted, using N-aminopyrrolidine instead of N-aminomorpholine, to the title compound (40 mg, 17%) which was obtained as an off white solid. MS: m/e=359.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[N+:17]([O-])([OH:19])=[O:18]>C(OC(=O)C)(=O)C.C(O)(=O)C>[F:1][C:2]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:5]2[N:6]([CH2:11][CH:12]([CH3:13])[CH3:14])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CC(C)CN1C(=O)COc2cc(F)ccc21
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(C)CN1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To 2.50 g (11.2 mmol) of 7-fluoro-4-isobutyl-2H-1,4-benzoxazin-3(4H)-one in 25 ml of acetic anhydride was added dropwise over 10 min. a solution of 2.5 g (26.9 mmol) of 70% nitric acid in 5 ml of glacial acetic acid. After the addition was complete, the reaction was stirred for 1 hour at room temperature then it was quenched by pouring into 50 ml of ice/water. The resulting white precipitate was collected by vacuum filtration and dried in a vacuum oven at 60° C. overnight to yield 2.71 g (90% yield) of the desired nitrated product, m.p. 108°-110° C.
Reaction SMILES: N[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:3]=1.C(O)(=O)C.[BrH:27].N([O-])=O.[Na+]>O>[Br:27][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:3]=1
Reactant: Br
Reactant: CCOC(=O)c1ccc(N)cc1-c1ccc(OC)c(OC)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(Br)cc1-c1ccc(OC)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
Ethyl 4-amino-2-(3,4-dimethoxyphenyl)benzoate (20.0 g; 0.066 mole; compound 252) and acetic acid (200 ml) are introduced into a 1000 ml three-necked flask. After dissolution, 47% strength hydrobromic acid (60 ml) is added, the mixture is cooled to 0° C. and then distilled water (150 ml) is added. Sodium nitrite (4.6 g; 0.066 mole) dissolved in water (30 ml) is poured in. Stirring is continued at between 0° and 5° C. for one hour, then the mixture is poured onto a solution of cuprous bromide (9.5 g; 0.066 mole) in 47% strength hydrobromic acid (100 ml). The reaction mixture is heated to 65% for one hour, then poured into water. The precipitate formed is filtered, rinsed with water and then dried in the air. Ethyl 4-bromo-2-(3,4-dimethoxyphenyl)benzoate (18.4 g; yield: 76.3%) is thus obtained, m.p. 53° C. (compound 250).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[F:11][C:12]([F:32])([F:31])[C:13]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[N:19]=[CH:18]2)=O.C(N(CC)CC)C.[BH4-].[Na+]>ClCCl.CO.[OH-].[Na+].Cl[Ti](Cl)(Cl)Cl>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][CH:13]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)[N:19]=[CH:18]2)[C:12]([F:31])([F:11])[F:32])([O-:3])=[O:2]
Reactant: O=C(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1NC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Reaction time: 20 h
Yield: 52.7 %

Procedure:
To a solution of 134 mg (0.97 mmol) of 2-nitroaniline in 5 mL of dichloromethane was added 300 mg (0.97 mmol) of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanone, 210 μL (2.9 mmol) of triethylamine, followed by 500 μL 0.5 mmol) of TiCl4. The mixture stirred for 20 hours and was then diluted with methanol followed by 40 mg (1.0 mmol) of sodium borohydride. After 1 hour, the mixture was diluted with 50 mL of 1N aqueous NaOH and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by Combiflash chromatography using EtOAc-hexanes (0-70% gradient) to afford 220 mg (53%) of the title compound as a yellow foam. MS m/z 431 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[C:18]([CH3:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=3)[S:10][C:9]=2[CH:21]=1)=[O:4].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][NH2:38])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:22]([O:26][C:27]([N:29]1[CH2:30][CH2:31][N:32]([CH2:35][CH2:36][CH2:37][NH:38][C:15]2[N:14]=[C:13]([C:11]3[S:10][C:9]4[CH:21]=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[CH:6]=[CH:7][C:8]=4[CH:12]=3)[C:18]([CH3:19])=[CH:17][N:16]=2)[CH2:33][CH2:34]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN)CC1
Reactant: CNC(=O)c1ccc2cc(-c3nc(Cl)ncc3C)sc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CNC(=O)c1ccc2cc(-c3nc(NCCCN4CCN(C(=O)OC(C)(C)C)CC4)ncc3C)sc2c1
Temperature: 95 °C
Yield: 43.9 %

Procedure:
A mixture of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-6-carboxylic acid methylamide (263 mg, 0.830 mmol), 4-(3-aminopropyl)-piperazine-1-carboxylic acid tert-butyl ester (358 mg, 1.47 mmol) and diisopropylethylamine (0.44 mL) in 1,4-dioxane (10 mL) is heated at 95° C. for 20 hours. The solvent is removed after cooling and the residue is subjected to chromatography on silica gel, eluting with 2.0 M NH3/MeOH in dichloromethane 0-10%, to give 4-{3-[5-methyl-4-(6-methylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-propyl}-piperazine-1-carboxylic acid tert-butyl ester (191 mg, 44% yield). The intermediate is dissolved in THF (8 mL) and 5 N hydrochloric acid (5 mL) is added. The solution is heated at 70° C. for 4.5 hours and then cooled before evaporating the solvent. Methanol is added to the residue and the mixture is sonicated for 30 minutes. The solid is filtered and washed with diethyl ether, then dried in a vacuum oven at 50° C. for 18 hours to give the title compound (129 mg, 66% yield). ES+(m/z) 425 [M(free base)+H].
Reaction SMILES: [C:1]([Cl:5])(Cl)([Cl:3])[Cl:2].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=1>>[Cl:10][C:11]1[CH:12]=[C:13]([Cl:18])[C:14]([F:17])=[CH:15][C:16]=1[C:1]([Cl:5])([Cl:3])[Cl:2]
Reactant: Fc1ccc(Cl)cc1Cl
Reactant: ClC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Fc1cc(C(Cl)(Cl)Cl)c(Cl)cc1Cl
Yield: 62.7 %

Procedure:
Into a 200 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel, 97 ml (1 mol) of carbon tetrachloride and 26.7 g (0.2 mol) of aluminum chloride were charged, and 16.5 g (0.1 mol) of 1,3-dichloro-4-fluorobenzene was dropwised added thereto under reflux. Thereafter, the mixture was reacted for 20 minutes. Post treatment was conducted in the same manner as in Example 4 to obtain 17.7 g (yield: 62.6%) of 2.4-dichloro-5-fluorobenzotrichloride.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[C:10]2=[CH:11][CH:12]=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.[Cl-].[NH4+]>O1CCCC1.CO.[Zn]>[F:1][C:2]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[C:10]2=[CH:11][CH:12]=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ncnn3cccc23)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ncnn3cccc23)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)pyrrolo[2,1-f][1,2,4]triazine (4.25 g, 15.5 mmol) in 40 mL of tetrahydrofuran and 60 mL of methanol at 0° C. was added zinc dust (3.04 g, 46.5 mmol, <10 micron) followed by ammonium chloride (2.49 g, 46.5 mmol). The mixture was stirred at room temperature overnight. Additional zinc dust (6.08 g, 93 mmol) and ammonium chloride (5.0 g, 93 mmol) were added and the reaction was allowed to stir at room temperature for 4 h. The heterogeneous mixture was filtered through a thin pad of Celite ® with methanol and the filtrate was concentrated in vacuo. Purification by flash chromatography on silica gel (SiO2, EtOAc/Hexane 1:1) gave the title compound (3.5 g, 92%) as a yellow foam. 1H NMR (CDCl3) δ 7.92 (s, 1H), 7.70 (dd, 1H, J=2.5, 1.6 Hz), 6.98 (t, 1H, J=8.5 Hz), 6.92 (dd, 1H, J=4.4, 1.4 Hz), 6.77 (m, 1H), 6.42 (m, 2H), 3.71 (br s, 2H); MS(ESI+) m/z 245.2 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([C:10]([OH:12])=O)=[C:4]2[CH2:3][CH2:2]1.[C:13]([O:17][C:18]([N:20]1[C@H:27]([CH2:28][NH2:29])[CH2:26][C@H:25]2[C@@H:21]1[CH2:22][CH2:23][CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[C@H:27]([CH2:28][NH:29][C:10]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[O:1][CH2:2][CH2:3][C:4]=23)=[O:12])[CH2:26][C@H:25]2[C@@H:21]1[CH2:22][CH2:23][CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C(O)c1cccc2c1CCO2
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2CCC[C@@H]21
Product: CC(C)(C)OC(=O)N1[C@H](CNC(=O)c2cccc3c2CCO3)C[C@@H]2CCC[C@@H]21

Procedure:
prepared by reaction of 2,3-Dihydro-benzofuran-4-carboxylic acid with (1S,3S,5S)-3-aminomethyl-2-azabicyclo[3.3.0]octane-2-carboxylic acid tert-butyl ester. LC-MS: tR=1.00 min; [M+H]+=387.1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Li]CCCC.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]([C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[O:9][CH3:10])([OH:29])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(Cl)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C1(O)CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-4-chloroanisole (1a, 51 g, 0.23 mol) in THF (500 mL) was added dropwise n-BuLi (2.5 M in hexane, 138 mL, 0.345 mol) at −78° C. under nitrogen atmosphere. After being stirred at −78° C. for 1 h, 1-benzyl-piperidin-4-one (42 g, 0.22 mol) was added dropwise. After addition, the mixture was stirred at this temperature for 1 h, and then warmed to room temperature. The reaction was quenched with saturated NH4Cl (300 mL) and the separated aqueous layer was extracted with ethyl acetate (150 mL×3). The combined extracts were washed with water and brine, dried over Na2SO4, concentrated to dryness. The residue was purified by silica gel column to obtain 1-benzyl-4-(5-chloro-2-methoxy-phenyl)-piperidin-4-ol 1b as a white solid. 1H NMR (CDCl3): δ 7.37-7.24 (m, 6H), 7.21 (q, J1=8.8 Hz, J2=2.8 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 3.88 (s, 3H), 3.80 (s, 1H), 3.59 (s, 2, H), 2.77-2.74 (m, 2, H), 2.59-2.54 (t, 2H), 2.13-2.06 (m, 2H), 2.00-1.96 (m, 2H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Cl.[C:21](=[O:24])([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][O:24][C:21]1[CH:6]=[C:5]([CH:4]=[CH:3][CH:2]=1)[C:10]#[N:1]
Reactant: O=C([O-])[O-]
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(OCc2cccc(OCc3ccc4ccccc4n3)c2)c1

Procedure:
A solution of 0.65 g (5.4 mmol) 3-hydroxybenzoinitirle, 1.5 g (5.3 mmol) of 3-(2-quinolinylmethyloxy)benzyl chloride, and 0.75 g (5.4 mmol) of potassium carbonate in 15 ml of DMF is heated at 60° C. overnight. The reaction mixture is poured into water. The precipitated product is collected on a filter and purified by dry column chromatography to give 3-[3-(2-quinolinylmethyloxy)benzyloxy]benzonitrile. (M.P. 86°-87° C.)
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]#[N:18])=[CH:7][CH:6]=1)C(C)=O.[N+:19]([O-])([OH:21])=[O:20]>S(=O)(=O)(O)O>[C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([NH2:1])=[CH:6][C:7]=1[N+:19]([O-:21])=[O:20])#[N:18]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(-c2ccccc2C#N)cc1
Agent: O=S(=O)(O)O
Product: N#Cc1ccccc1-c1ccc(N)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
4'-Acetamino-2-cyanobiphenyl (0.265 moles, 62.47 g.) was added at -15° to -20° C. to 600 ml of concentrated sulfuric acid. While maintaining the temperature below -15° C., nitric acid (0.278 moles, 17.5 g of 90%) in 200 ml of concentrated sulfuric acid was added dropwise. The reaction was stirred for 30 minutes following the addition and then for 3 hours at room temperature. The reaction was poured onto ice with vigorous stirring. The precipitate was filtered and dried. The solid was stirred in methanol (6 liters) and 2N sodium hydroxide (11 liters) for 6 hours, filtered and dried. The reaction produced 60 g of 4-(2-Cyanophenyl)-3-nitroaniiine. (MS)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][N:6]=1)(=[O:3])[CH3:2].C(N(CCCC)CCCC)CCC.[C:25]([OH:29])(=[O:28])[CH:26]=[CH2:27].Cl>C1(C)C(C)=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:1]([NH:4][C:5]1[N:6]=[CH:7][C:8](/[CH:27]=[CH:26]/[C:25]([OH:29])=[O:28])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: C=CC(=O)O
Reactant: CC(=O)Nc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Product: CC(=O)Nc1ccc(/C=C/C(=O)O)cn1
Reaction time: 7 h
Yield: 75.2 %

Procedure:
To a mixture of 2-acetamido-5-bromopyridine (240 mg), tri-n-butylamine (456 mg), palladium(II) acetate (0.13 mg) and triphenylphosphine (1.5 mg) in xylene (0.48 ml) was dropwise added acrylic acid (97 mg) at 150° C., and the mixture was stirred for 7 hours at the same temperature. After cooling the mixture, water was added thereto, and the mixture was adjusted to pH4 with hydrochloric acid. The precipitate was collected by filtration, washed with xylene and water, and dried to give (E)-3-(6-acetamidopyridin-3-yl)acrylic acid (173 mg) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:19][C:20]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)[S:22][N:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][CH:28]4[CH2:27][CH2:26][N:25]([C:23]5[S:22][N:21]=[C:20]([CH3:19])[N:24]=5)[CH2:30][CH2:29]4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: Nc1nc2c(-c3ccc(F)c(Cl)c3)cccn2n1
Product: Cc1nsc(N2CCC(Nc3nc4c(-c5ccc(F)c(Cl)c5)cccn4n3)CC2)n1

Procedure:
Prepared in analogy to example 1h, starting from 8-(3-Chloro-4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one. The title compound was obtained as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[C:14]12([NH2:24])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>C(#N)C>[C:14]12([NH:24][CH2:2][C:3]([N:5]3[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]3[C:12]#[N:13])=[O:4])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC12CC3CC(CC(C3)C1)C2
Reaction time: 48 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g, 0.20 mmol) in acetonitrile (3 mL) at room temperature under nitrogen was added 1-adamantanamine (0.06 g, 0.408 mmol). The reaction mixture was stirred for two days and then concentrated under reduced pressure. The residue was flash chromatographed with 2% MeOH/CH2Cl2 to provide the titled compound. MS (DCI) m/z 312 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH:19]1[CH:24]=[C:23]([Cl:25])[C:22]([CH2:26]Br)=[C:21]([Cl:28])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:25][C:23]1[CH:24]=[CH:19][CH:20]=[C:21]([Cl:28])[C:22]=1[CH2:26][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2c(Cl)cccc2Cl)CCCC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.9 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (973 mg, 4.0 mM), a-bromo-2,6-dichlorotoluene (1.19 g, 4.8 mM), and potassium carbonate (553 mg, 4.0 mM) in 10 mL DMF was stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate, washed with H2O, 1 N HCl, H2O, saturated NaHCO3, H2O, and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated. The residue was purified by column chromatography on silica gel (elution with methylene chloride/ethyl acetate) to afford 900 mg (56%) of the 9-[(2,6-dichlorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a white foam. 1H NMR (CDCl3) δ7.4-7.2 (m, 6H), 5.6 (s, 2H), 4.0 (s, 3H), 2.9 (t, 2H, J=6 Hz), 2.55 (t, 2H, J=6 Hz), and 2.2 (m, 2H). IR (KBr, cm−1) 1725 and 1652. MS (ES) m/e 400, 402, 404.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:13]([O:25][CH3:26])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:34]=[C:33]([Cl:35])[C:32]([O:36][CH3:37])=[CH:31][C:29]=1[NH2:30].Cl.N1C=CC=CC=1>C(O)(C)C>[ClH:1].[ClH:27].[Cl:27][C:28]1[CH:34]=[C:33]([Cl:35])[C:32]([O:36][CH3:37])=[CH:31][C:29]=1[NH:30][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[C:13]([O:25][CH3:26])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: COc1cc2cc3c(Cl)ncnc3cc2cc1OCCN1CCOCC1
Agent: Cl
Solvent: CC(C)O
Solvent: c1ccncc1
Product: COc1cc(Nc2ncnc3cc4cc(OCCN5CCOCC5)c(OC)cc4cc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 61.9 %

Procedure:
To a suspension of 0.05 g (0.133 mmol) of 4-chloro-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinazoline in 2 mL of isopropanol is added 0.031 g (0.161 mmol) of 2,4-dichloro-5-methoxyaniline and 0.016 g (0.133 mmol) of pyridine hydrochloride. The mixture is brought to reflux for 2 hours, then allowed to cool to room temperature. A yellow precipitate formed, which is filtered and washed with cold isopropanol. Drying in vacuo provided 0.030 g of (2,4-dichloro-5-methoxyphenyl)-[7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinazolin-4-yl]-amine dihydrochloride as a yellow solid, mp 258-260° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=O)[C:2]1=[O:11].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[Cl:20])[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([N:16]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:11])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C1Nc2ccccc2C1=O
Product: O=C1Nc2ccccc2C1=Nc1ccc(Cl)c(Cl)c1
Temperature: 75 °C
Yield: 95.2 %

Procedure:
A mixture of 1H-indole-2,3-dione (10.3 g, 70 mmol), 3,4-dichloroaniline (17.0 g, 70 mmol) was heated at 75° C. for 2 hours in a tightly sealed round bottom flask under argon and cooled to room temperature. The solid was recrystallized from CH2Cl2, giving the desired product (19.4 g, 90%).
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(NC(C)C)(C)C.ClC(OC)=O.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])(=[O:42])=[O:41])=[CH:36][CH:35]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([S:40]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])(=[O:42])=[O:41])=[CH:36][CH:35]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reactant: CCOC(=O)CCCS(=O)(=O)c1ccc(N)cc1
Agent: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CCOC(=O)CCCS(=O)(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxylic acid (Intermediate 13, 130 mg; 0.47 mmol) in DCM was treated with diisopropylamine (90 mL; 0.52 mmol) and methyl chloroformate (40 mL; 0.52 mmol). After stirring at 0° C. for 15 minutes, ethyl 4-(4-aminophenylsulfonyl)butanoate (Intermediate 48, 130 mg; 0.48 mmol) was added. After stirring at 0° C. for 30 minutes and RT for 1 hour, saturated sodium bicarbonate solution was added and the mixture stirred for 15 minutes. DCM was added and the layers separated. The organic extract was filtered through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>C(O)C>[Cl:10][CH2:11][C:12]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][CH:14]=1
Reactant: NC(=O)c1ccccc1
Reactant: O=C(CCl)CCl
Solvent: CCO
Product: ClCc1coc(-c2ccccc2)n1
Yield: 28.8 %

Procedure:
Benzamide (10.0 g) and 1,3-dichloroacetone (10.5 g) were dissolved in ethanol (100 mL), and the mixture was refluxed for 8 hr. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=7:1) to give the title compound (4.6 g) as a white solid.