Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][CH:16]=[O:17])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH3:18][Mg]I>CCOCC>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[CH2:15][CH:16]([OH:17])[CH3:18])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: C[Mg]I
Reactant: O=CCc1c2ccccc2cc2ccccc12
Solvent: CCOCC
Product: CC(O)Cc1c2ccccc2cc2ccccc12
Yield: 88.9 %

Procedure:
9-anthrylacetaldehyde (1.1 g; 5 mmoles) was Soxhlet--extracted for a period of 6 hours in an ether solution (100 ml) of methylmagnesium iodide (30 mmoles; prepared from 0.72 g of magnesium). Work up as described above gave 1.05 g (89%) of 1-(9-anthryl)-2-propanol as pale yellow needle shaped crystals, mp 105°-107° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: C1COCCN1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCOCC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and morpholine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=373.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:20]C)[C:10](=[O:19])[N:11]([CH3:18])[C:12]=2[CH2:16][CH3:17])[C:7]1=[O:22].[N+](=[CH2:29])=[N-]>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:20])[C:10](=[O:19])[N:11]([CH3:18])[C:12]=2[CH:16]2[CH2:29][CH2:17]2)[C:7]1=[O:22]
Reactant: C=[N+]=[N-]
Reactant: CCc1c2c(c(OC)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: Cn1c(C2CC2)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 2-(3-chloro-4-fluorobenzyl)-5-vinyl-8-methoxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione (0.12 g, 0.32 mmol; Example 83, step 2) in diethyl ether (5 mL), a solution of diazomethane (˜3 mmol) in diethyl ether was added. Catalytic amount of palladium (II) acetate was added and the mixture was stirred at the same temperature for 30 minutes. The product mixture was filtered and concentrated under vacuum. The residue was subjected to preparative reverse phase HPLC purification. Collection and lyophilization of appropriate fractions provide the cyclopropanation intermediate. Following the demethylation procedure described in Example 83, step 3, the above intermediate was converted to the titled compound.
Reaction SMILES: [NH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[C:2]1=O.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[N:3]2[C:12]3[C:7]([CH2:6][CH2:5][CH2:4]2)=[CH:8][CH:9]=[CH:10][C:11]=3[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cccc3c2n1CCC3
Product: Clc1nc2cccc3c2n1CCC3

Procedure:
7.6 g (0.0436 mol) of 5,6-dihydro-4H-imidazo[4,5,1-ij]quino1-2(1H)-one are heated in the presence of 70 ml of phosphoryl chloride at the reflux 20 temperature for 3 hours. The solvent is evaporated to dryness and the residue is taken up in ice. The pH of the reaction mixture is adjusted to 8 with a concentrated sodium hydroxide solution and extraction is carried out with dichloromethane. The organic phase is dried over sodium sulphate and the solvent evaporated to dryness. The residue is purified by chromatography on a column of silica gel, the eluent being an ethyl acetate/hexane (30/70) mixture. There are obtained 5.8 g of product which is used as is in the following stage.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH:31](=O)/[CH:32]=[CH:33]/[CH2:34][CH2:35][CH3:36]>>[C:2]([OH:4])(=[O:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:31][CH:32]=[CH:33][CH2:34][CH2:35][CH3:36]
Reactant: O=C(O)CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC/C=C/C=O
Agent: [Br-]
Product: CCCC=CC=CCCCCCCC(=O)O
Yield: 43.9 %

Procedure:
This compound was synthesized from 7-carboxyheptyltriphenylphosphonium bromide (9.71 g, 20 mmol) and 2-trans-hexenal (1.96 g, 20 mmol) in 10% hexamethylphosphoric triamide (HMPA)-THF (100 mL) by a Wittig reaction. Kugelrohr distillation yielded the product (1.97 g, 44%) as a yellow oil (bp 123-126° C./0.01 torr). IR: 3450-2500, 1720 cm-1 ; 1H-NMR; 0.95 (t, 3H), 1.35 (m, 8H), 1.62 m, 2H), 2.05 (m, 4H), 2.32 (t, 2H), 5.23 (m, 1H), 5.60 (m, 1H), 5.90 (m, 1H), 6.05 (m, 1H), 10.50 (bs, 1H). Anal. Calcd. for C14H24O2 : C, 74.95, H, 10.78%; Found: C, 75.01, H, 10.80%.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([CH:17]=[CH:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)#[N:16].N12CCCN=C1CCCCC2>C(#N)C>[C:15]([CH2:17][CH:18]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH2:19][CH:20]1[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]1)#[N:16]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(CC=CC#N)CC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(CC(CC#N)n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.28 g, 6.60 mmol) in acetonitrile (33.0 mL) was added tert-butyl 4-(3-cyanoprop-2-en-1-yl)piperidine-1-carboxylate (3.30 g, 13.2 mmol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.987 mL, 6.60 mmol). The resulting mixture was stirred at room temperature overnight. After evaporating the reaction mixture to dryness, the residue was purified on silica gel, eluting with 0-50% EtOAc in hexanes, to give the desired product (2.35 g, 80%). LCMS (M+H) 445.2
Reaction SMILES: C(O[C:4]([C:6]1[CH:15]=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])C.[CH:16]1([C:19]([CH3:21])=[O:20])[CH2:18][CH2:17]1.C[O-].[Na+]>C1C=CC=CC=1>[CH:16]1([C:19](=[O:20])[CH2:21][C:4]([C:6]2[CH:15]=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)=[O:5])[CH2:18][CH2:17]1
Reactant: CCOC(=O)c1cnc2ccccc2n1
Reactant: CC(=O)C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(CC(=O)C1CC1)c1cnc2ccccc2n1

Procedure:
A mixture of 3.0 g. of ethyl-2-quinoxalate, 1.7 g. of cyclopropylmethyl ketone and 0.9 g. of sodium methoxide in 100 ml. of benzene is heated under reflux for 4 hours. The mixture is diluted with 100 ml. of water and the benzene phase is separated. The aqueous solution is made weakly acidic with dilute hydrochloric acid and extracted with chloroform. The chloroform solution is dried over magnesium sulfate and concentrated under reduced pressure to yield straw-colored crystals, which are recrystallized from acetonitrile to provide cream-colored crystals, melting point 113°-115°C.
Reaction SMILES: [C:1]([C:11]1[N:15]([CH3:16])[C:14]([CH2:17][C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=1)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C>O>[C:1]([C:11]1[N:15]([CH3:16])[C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(C(=O)c2ccc(OC)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)c2ccc(CC(=O)O)n2C)cc1

Procedure:
A solution of 3.00 g. (0.0105 mole) of methyl 5-(p-anisoyl)-1-methylpyrrole-2-acetate in 12 ml. (0.012 mole) of 1N sodium hydroxide solution and 5 ml. of 95% ethanol is refluxed for 30 minutes. The solution is diluted with water, and the ethanol is evaporated in vacuo. The solution is filtered, and the filtrate acidified with dilute hydrochloric acid. The precipitated solid is collected by filtration, dried and recrystallized from methanol-water to give white 5-(p-anisoyl)-1-methylpyrrole-2-acetic acid, m.p. 170-171° C. Analysis: Calcd. for C15H15NO4 : C, 65.92; H, 5.53; N, 5.13%. Found: C, 66.01; H, 5.62; N, 5.12%
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.O.[F:11][C:12]([F:17])([F:16])[CH2:13][NH:14][NH2:15]>C(O)(=O)C>[F:11][C:12]([F:17])([F:16])[CH2:13][N:14]1[C:1](=[O:7])[CH2:2][C:3]([CH3:5])=[N:15]1
Reactant: NNCC(F)(F)F
Reactant: CCOC(=O)CC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC1=NN(CC(F)(F)F)C(=O)C1

Procedure:
0.25 Mole (32.5 g) of ethyl acetoacetate and 0.25 mole (42 g) of 2,2,2-trifluoroethylhydrazine hydrate were stirred and refluxed for 2 hours in 125 ml of acetic acid. The acetic acid was distilled off in vacuo. The distillation residue was rubbed with water and recrystallized from methanol.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=1.Br[CH2:13][CH2:14][O:15][CH3:16].O>CN(C=O)C>[CH3:16][O:15][CH2:14][CH2:13][N:11]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[S:2][CH3:1]
Reactant: CSc1nc2cccnc2[nH]1
Reactant: COCCBr
Solvent: O
Solvent: CN(C)C=O
Product: COCCn1c(SC)nc2cccnc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
A mixture of 2-(methylthio)-3H-imidazo[4,5-b]pyridine (400 mg) and 1-bromo-2-methoxyethane (370 mg) in DMF (7 mL) was stirred at 80° C. for 3 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (200 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([C:12]2[N:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49]Cl)[CH:44]=1.O>C(#N)C>[Cl:1][C:2]1[C:10]([O:11][CH2:49][C:45]2[CH:44]=[N:43][CH:48]=[CH:47][CH:46]=2)=[CH:9][C:8]([C:12]2[N:13]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35]
Reactant: ClCc1cccnc1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(O)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCc3cccnc3)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 50 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
4-Chloro-5-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (70.0 mg, 0.141 mmol) was suspended in acetonitrile (3.5 mL), and the suspension was added with cesium carbonate (91.9 mg, 0.282 mmol) and 3-pyridylmethyl chloride hydrochloride (23.1 mg, 0.141 mmol), followed by stirring at 50° C. for 12 hours under nitrogen atmosphere. The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-chloro-5-(3-pyridylmethoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (49.7 mg, yield 60%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH:25]([C:27]1[N:28]=[C:29]([CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)[S:30][CH:31]=1)=O.C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[Br:21][C:20]([Br:24])=[CH:25][C:27]1[N:28]=[C:29]([CH:32]2[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:37]2)[S:30][CH:31]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C=C(Br)Br)cs2)CC1
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
To a solution of triphenylphosphine (7.08 g, 27 mmol) in anhydrous dichloromethane (11 ml) was added dropwise a solution of carbon tetrabromide (4.3 g, 13 mmol) in anhydrous dichloromethane (5 ml) at 10° C., and the mixture was stirred at the same temperature for 15 mins. Stirring was stopped, the supernatant of the reaction mixture was collected, and a solution of tert-butyl 4-(4-formyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (1.0 g, 3.4 mmol) in anhydrous dichloromethane (11 ml) was added dropwise at 10° C. After stirring at 5-10° C. for 40 mins, triethylamine (4 ml) and saturated aqueous sodium hydrogen carbonate solution (0.5 ml) were added. The mixture was filtered through a Celite pad, and the insoluble material was washed with dichloromethane. The filtrate and washing solution were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to give tert-butyl 4-[4-(2,2-dibromovinyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (1.5 g, yield 97%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11](C(OCC3C=CC=CC=3)(O)C)[CH:12]=[CH:13][C:14]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>N1C=CC=CC=1>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:15][C:14]2[C:9]([O:8][CH2:7][C:6]3[CH:36]=[CH:37][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:10][CH:11]=[CH:12][C:13]=2[CH:38]([OH:40])[CH3:39])=[CH:18][CH:19]=1
Reactant: COc1ccc(COc2ccc(C(C)(O)OCc3ccccc3)cc2OCc2ccc(OC)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(COc2cccc(C(C)O)c2OCc2ccc(OC)cc2)cc1
Temperature: 0 °C
Yield: 91.5 %

Procedure:
To an ice cold solution of α-chloro-3,4-dihydroxypropiophenone (2) (1.0 g; 4.98 mMol.) in pyridine (3 ml) is added acetic anhydride (1.2 ml) After 1.5 hours at room temperature, the reaction mixture is concentrated under reduced pressure. The residue is dissolved in chloroform, washed with water, dried, and concentrated under reduced pressure to give α-chloro-2,3-diacetoxypropiopheonen (3) (1.3 g).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH3:11][C:12]([O:15][C:16](=O)[O:17]C(C)(C)C)([CH3:14])[CH3:13].C(N(CC)CC)C>CO>[OH:4][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][NH:1][C:16](=[O:17])[O:15][C:12]([CH3:14])([CH3:13])[CH3:11]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: NC[C@H](O)c1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 88.4 %

Procedure:
(R)-α-(Aminomethyl)benzenemethanol (1.70 g) and bis(1,1-dimethylethyl)carbonate (2.98 g) were dissolved in methanol (20 ml) and triethylamine (4.3 ml) added. The mixture was stirred at room temperature for 4 days and then concentrated to leave the sub-title compound as an oil (2.60 g).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Br:7].[CH2:8]([C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1)[CH3:9]>>[Br:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[CH:14]([C:13]1[CH:16]=[CH:17][C:10]([CH2:8][CH3:9])=[CH:11][CH:12]=1)[OH:15]
Reactant: CCc1ccc(C=O)cc1
Reactant: Brc1ccsc1Br
Product: CCc1ccc(C(O)c2sccc2Br)cc1

Procedure:
2,3-Dibromothiophene and 4-ethylbenzaldehyde were treated in a manner similar to Reference Example 1-(1) to give 3-bromo-2-thienyl-4-ethylphenylmethanol as yellow oil. APCI-Mass m/Z 279/281 (M+H−H2O).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19](Cl)[N:18]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:19]2[CH:20]=[N:21][CH:22]=[C:17]([Cl:16])[N:18]=2)[CH:10]([CH2:14][CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CCC1CN(Cc2ccccc2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC1CN(Cc2ccccc2)CCN1c1cncc(Cl)n1

Procedure:
The title compound was prepared according to the procedure of example 39, step 2, starting from the product obtained in step 1 above (4.60 g, 22.5 mmol), 2,6-dichloropyrazine (3.90 g, 26.2 mmol) and K2CO3 (6.22 g, 45.0 mmol). Yield: 6.15 g (86%). MS m/z 316/318 (M)+(35Cl/37Cl-isotope pattern). HRMS m/z calcd for C17H21ClN4 (M)+ 316.1455, found 316.1455.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8]P(=O)(OCC)OCC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:23](/[CH:24]=[CH:8]/[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:18][CH:17]=2)[CH:22]=1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reactant: COc1cccc(C=O)c1
Product: COc1cccc(/C=C/c2ccc([N+](=O)[O-])cc2)c1

Procedure:
In an analogous manner to that described in Example 36a), the reaction of diethyl (4-nitrobenzyl)phosphonate with 3-methoxybenzaldehyde yields the (E)-1-methoxy-3-[2-(4-nitrophenyl)ethenyl]-benzene as a yellow solid; MS: m/e=255 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([CH3:15])[CH:11]=3)[NH:6][C:5]=2[CH2:4][CH2:3]1.C(OCC)(=O)C>[Pd].C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([CH3:15])=[CH:9][CH:8]=3
Reactant: Cc1ccc2[nH]c3c(c2c1)CC(C)CC3
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: Cc1ccc2[nH]c3ccc(C)cc3c2c1
Temperature: 150 °C
Yield: 93.4 %

Procedure:
A mixture of 12.0 g (60.3 mmol) of 3,6-dimethyl-1,2,3,4,-tetrahydrocarbazole and 3.6 g of 10% palladium on charcoal (46-190, Strem Chemicals, Danvers, Mass.) in 120 ml xylene was refluxed vigorously (150° C) overnight. Addition of 200 ml of ethyl acetate, filtration of the cooled mixture through Celite 545 and evaporation of solvents gave 11.0 g (94%) of 3,6-dimethylcarbazole, mp 218°-21° C (lit. mp 217°-18° C).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH2:18]([C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1)[CH3:19]>CN1CCCC1=O.O>[CH2:18]([C:20]1[N:21]=[CH:22][C:23]([CH2:26][CH2:27][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:24][CH:25]=1)[CH3:19]
Reactant: C=Cc1ccc(CC)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1ccc(CCn2c3c(c4cc(C)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18 %

Procedure:
To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.15 g. 0.749 mmol) in N-methyl 2-pyrolidone (1.2 mL) was added powdered potassium hydroxide (0.42 g, 7.49 mmol) and allowed to stir for 10 min at RT. 2-Ethyl-5-vinyl-pyridine (0.299 g, 2.24 mmol) was added and stirred for further 18 h. at 100 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (7% McOH:DCM in silica 100-200 mesh, Diameter of column 2.5 cm, Height of silica—approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.045 g, 18% yield). 5-[2-(6-Ethyl-pyridin-3-yl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.040 g, 0.12 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.012 g, 0.096 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.030 g, 60% yield).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:20])[CH:8]=2)[N:3]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:20][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:11]([C:12]#[N:13])=[C:10]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#Cc1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: C1CCNCC1
Product: N#Cc1c(N2CCCCC2)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 27 step C from 2,6-dichloro-4-phenyl-quinoline-3-carbonitrile (prepared as described in example 27 step B) and piperidine. Yellow solid. MS (ESI): 348.2 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1F)[O:15][CH2:14][CH2:13][CH:12]2[C:20]([O:22][CH3:23])=[O:21])#[N:8].[OH:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][C:26]=1[CH3:38].Cl>CN1C(=O)CCC1>[C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([OH:31])=[O:30])=[CH:27][C:26]=1[CH3:38])[O:15][CH2:14][CH2:13][CH:12]2[C:20]([O:22][CH3:23])=[O:21])#[N:8]
Reactant: COC(=O)C1CCOc2cc(F)c(C#N)cc21
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3C)c(C#N)cc21
Temperature: 120 °C

Procedure:
A mixture of K2CO3 (0.026 g, 0.19 mmol), methyl 6-cyano-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (0.040 g, 0.17 mmol), and tert-butyl 4-hydroxy-3-methylbenzoate (0.039 g, 0.19 mmol) in 0.5 ml NMP was heated under argon at 120° C. for 24 hours. The reaction was cooled, poured into 10% aqueous HCl, and extracted with ethyl acetate. The organic extracts were dried with sodium sulfate and purified on silica gel. Elution with 25% ethyl acetate-hexanes provided material that still contained impurities. The mixture was deprotetcted with to 1:1 trifluoracetic acid-dichloromethane to provide the title compound (13 mg, still impure) which was used directly in the next step.
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[Cl:16][C:17]1[CH:36]=[CH:35][C:20]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:33][CH3:34])=[C:29](O)[CH:30]=3)[N:25]=[CH:24][CH:23]=2)=[C:19]([F:37])[CH:18]=1>N1C=CC=CC=1>[Cl:16][C:17]1[CH:36]=[CH:35][C:20]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:33][CH3:34])=[C:29]([O:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)=[C:19]([F:37])[CH:18]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cc2nccc(Nc3ccc(Cl)cc3F)c2cc1O
Solvent: c1ccncc1
Product: COc1cc2nccc(Nc3ccc(Cl)cc3F)c2cc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
Triflic anhydride (620 mg, 2.2 mmol) was added to 4-(4-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinoline (637 mg, 2 mmol) in pyridine (6 ml) at 0° C. over 5 minutes. The mixture was stirred 1 hour and left to warm up to ambient temperature. The volatiles were removed by evaporation and the residue was partitioned between ethyl acetate and water containing 1M hydrochloric acid. The organic layer was dried (MgSO4), insoluble materials were removed by filtration and the volatiles were removed by evaporation. The resulting crude oil was purified by flash chromatography eluting with ethyl acetate/isohexanes (1/9 increasing to 9/1). The volatiles were removed by evaporation and the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-methoxy-6-trifluoromethylsulphonyloxyquinoline (560 mg, 62%).