Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][N:34]=2)[CH:29]=[CH:28][C:27]=1[C:36](O)=[O:37]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:27]4[CH:28]=[CH:29][C:30]5[C:35](=[N:34][CH:33]=[CH:32][CH:31]=5)[N:26]=4)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1ccc2cccnc2n1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc5cccnc5n4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 1,8-naphthyridine-2-carboxylic acid as starting compounds. The crude product is purified by chromatography (silica gel and DCM/diethyl ether/methanol=49:49:3) to yield the title compound.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4/[CH:28]=[CH:29]/[N+:30]([O-:32])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]>O1CCOCC1.C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][N+:30]([O-:32])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(/C=C/[N+](=O)[O-])c[nH]c34)no2)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC[N+](=O)[O-])c[nH]c34)no2)cc1Cl
Temperature: 25 °C
Yield: 84.2 %

Procedure:
To a suspension of NaBH4 (0.7 g) in 1,4-dioxane (150 mL) and ethanol (50 mL) stirred in air at room temperature was added a solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-3-[(E)-2-nitroethenyl]-1H-indole (D82) (2.6 g) in 1,4-dioxane (150 mL) dropwise. The reaction mixture was stirred at 20° C. for 1 h. The excess NaBH4 was quenched with dilute H2SO4. The reaction solution was concentrated. Ethyl acetate (300 mL) was added to the residue, washed with water and brine, and then dried over MgSO4. Solvent was evaporated off to give the desired product 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-3-(2-nitroethyl)-1H-indole (D83) (2.2 g) as a yellow solid. δH (CDCl3, 400 MHz): 1.46 (6H, d), 3.55 (2H, t), 4.69-4.74 (3H, m), 7.07 (1H, d), 7.23 (1H, d), 7.30 (1H, t), 7.75 (1H, d), 8.08 (1H, dd), 8.12 (1H, d), 8.26 (1H, d), 9.74 (1H, s). MS (ES): C21H19ClN4O4 requires 426; found 427.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]>>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:28][CH2:29]3)=[N:22][CH:23]=1)=[CH:3][C:2]([C:42]1[CH:41]=[C:40]([F:53])[C:39]([OH:54])=[C:38]([Cl:37])[CH:43]=1)=[CH:11][CH:10]=2)(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CCCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Yield: 73.9 %

Procedure:
Following general procedure F, tert-butyl 4-[5-(6-bromo-3-butyrylquinolin-4-ylamino)pyridin-2-yl]piperazine-1-carboxylate (80 mg, 0.144 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (59 mg, 0.216 mmol) to afford the crude product (66 mg) as an orange solid: ESI MS m/z 620 [C33H35ClFN5O4+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=3)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:25])[C:6]=2[CH:26]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:25][C:7]1[C:6]2[CH:26]=[C:2]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:3]=[CH:4][C:5]=2[S:9][C:8]=1[S:10]([NH:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:12])=[O:11]
Reactant: CCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Br)cc3c2C)c1
Reactant: C1CCNC1
Product: CCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(N4CCCC4)cc3c2C)c1

Procedure:
The intermediate ethyl 3-{[(3-methyl-5-pyrrolidin-1-yl-1-benzothiophen-2-yl)sulfonyl]amino}benzoate was prepared from ethyl 3-{[(5-bromo-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate (Intermediate 18) (45 mg, 0.1 mmol) and pyrrolidine (8 mg, 0.12 mmol) according to General Procedure 4, described in Example 45.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][C:4]1[S:13][C:7]2[N:8]=[CH:9][NH:10][C:11](=O)[C:6]=2[CH:5]=1.O=P(Cl)(Cl)[Cl:18]>CN(C=O)C>[Cl:18][C:11]1[C:6]2[CH:5]=[C:4]([CH2:3][C:2]([F:15])([F:14])[F:1])[S:13][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2sc(CC(F)(F)F)cc12
Solvent: CN(C)C=O
Product: FC(F)(F)Cc1cc2c(Cl)ncnc2s1

Procedure:
5.7 g of 6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4(3H)-one was added to 16 mL of POCl3 with one drop of DMF. The heterogeneous mixture was refluxed for 3 hs and then evaporated. The residue was quenched with ice and saturated ammonia solution and extracted with chloroform. Combined extracts were evaporated with silica gel and loaded on a short silica gel column. The column was eluted with hexane-ethyl acetate (5:1) to afford 5.9 g of 4-chloro-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine. 1H NMR CDCl3 (300 MHz): 8.86 (s, 1H), 7.39 (s, 1H), 3.76 (q, 2H, J9.9 Hz). 13C NMR CDCl3 (75 MHz): 169.0, 154.7, 153.2, 129.9, 125.3, 123.5, 121.3, 35.9 (q, J33.0 Hz).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]1[CH2:16][NH:15][C:14](=O)[CH2:13]1>C1COCC1>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]1[CH2:13][CH2:14][NH:15][CH2:16]1
Reactant: O=C1CC(c2cccs2)CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1csc(C2CCNC2)c1

Procedure:
To a suspension of LiAlH4 (0.46 g) in THF (25 ml) was added the product of Example 134 (1.0 g) in THF (30 ml). After the addition was complete the reaction was heated at reflux for 4 hrs.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.P(Cl)(Cl)([Cl:15])=O.C1(C)C=CC=CC=1.C(N(CC)CC)C>CC(C)=O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[Cl:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ccc(I)cc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: Clc1ncnc2ccc(I)cc12
Temperature: 25 °C
Yield: 88.7 %

Procedure:
In a 500 mL-volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed 50.0 g (184 mmol) of 6-iodoquinazolin-4-one, 33.8 g (221 mmol) of phosphorus oxychloride, and 300 mL of toluene in a nitrogen atmosphere. While the mixture was stirred at room temperature, 22.3 g (221 mmol) of triethylamine was slowly added. The resulting mixture was heated at 60° C. for 30 minutes and then heated at 75° C. for 2 hours, for carrying out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature, and 50 mL of acetone was added. The mixture was then cooled to 0° C. and stirred for 30 minutes. Thus precipitated pale yellow crystalline product of 6-iodo-4-chloroquinazoline was collected by filtration. Subsequently, the crystalline product was placed in 200 mL of water, and 9 mL of aqueous sodium hydroxide (1 mol/L) was added. The aqueous mixture (pH 10-11) was stirred for 30 minutes at room temperature. The crystalline product was collected by filtration, washed successively with 100 mL of acetone, 200 mL of water and 100 mL of acetone, and dried at 60° C. under reduced pressure, to give 47.4 g (isolated yield: 89%, purity 99% in terms of area percentage determined by high performance liquid chromatography) of 6-iodo-4-chloroquinazoline as a yellowish crystalline product.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]([F:46])([F:45])[C:33]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:34]=1[CH2:35]Br.Cl>CC(N(C)C)=O>[F:31][C:32]([F:45])([F:46])[C:33]1[CH:40]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:38]=[CH:37][C:34]=1[CH2:35][N:9]1[C:10](=[O:23])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:12]([OH:13])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]1=[O:24]
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1=O
Reaction time: 8 h
Yield: 33.5 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 2,4-bis(trifluoromethyl)benzyl bromide (375 uL, 2.0 mmoles) in dimethylacetamide (6 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from acetic acid-water gave the title compound (180 mg, 34%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (br. s., 1 H), 8.06 (s, 1 H), 7.98 (d, J=8.59 Hz, 1 H), 7.53 (d, J=8.34 Hz, 1 H), 5.23 (s, 2 H), 4.64 (t, J=12.00 Hz, 1 H), 4.13 (d, J=5.56 Hz, 2 H), 2.24 (q, 2 H), 1.78 (d, J=12.63 Hz, 2 H), 1.52-1.73 (m, 3 H), 1.28 (q, J=13.05 Hz, 2 H), 1.10 (q, 1 H).
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH3:25])=[CH:19][C:18]=3[OH:26])[C:9]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34](=O)([O-])[O-].[Cs+].[Cs+].ClCI>O1CCCC1>[C:28]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH3:25])=[CH:19][C:18]=4[O:26][CH2:34]3)[C:9]2=[O:27])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C([O-])[O-]
Agent: ClCI
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
To a mixture of 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one (10.6 g, 24.4 mmol) and cesium carbonate (23.8 g, 73.1 mmol) in tetrahydrofuran (100 mL) was added chloroiodomethane (6.35 g, 36.6 mmol) under nitrogen. The mixture was stirred at ambient temperature for 3 h, then filtered through a pad of silica and rinsed with tetrahydrofuran (500 mL). The filtrate was concentrated in vacuo to dryness. The residue was recrystallized from diethyl ether (20 mL) to afford 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (7.9 g, 72%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.41-7.27 (m, 10H), 7.15 (dd, J=7.1, 1.5 Hz, 1H), 7.07 (s, 1H), 7.05-6.92 (m, 2H), 6.55-6.49 (m, 2H), 6.34 (s, 1H), 4.86 (ABq, 2H), 3.80 (s, 3H), 2.01 (s, 3H); 13C NMR (75 MHz, CDCl3) δ178.1, 160.2, 159.2, 141.8, 137.8, 137.4, 132.9, 128.70, 128.66, 128.48, 128.46, 128.2, 128.0, 127.9, 124.2, 123.8, 123.1, 119.6, 112.2, 93.8, 80.4, 58.7, 57.7, 55.6, 16.1; MS (ES+) m/z 448.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].Cl.[CH3:12][NH:13][O:14][CH3:15].CN(C)CCCN=C=NCC.N1C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([N:13]([O:14][CH3:15])[CH3:12])=[O:6]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 82.4 %

Procedure:
In a round-bottomed flask, 2.0 g of 2-bromoisonicotinic acid, 1.1 g of N,O-dimethylhydroxylamine hydrochloride, 3.8 g of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide and 3.2 ml of pyridine are placed in 50 ml of tetrahydrofuran. The mixture is stirred at ambient temperature for 40 h. The mixture is concentrated, and the residue is taken up in 50 ml of ethyl acetate and 50 ml of water. The organic phase is washed with 50 ml of a 1N solution of sodium hydroxide and 50 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. 2.0 g of compound are obtained.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[CH3:6][NH:7][C:8](=[O:21])[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1CO)=[N:10][O:11][CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[CH3:6][NH:7][C:8](=[O:21])[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:1][Br:5])=[N:10][O:11][CH3:12]
Reactant: CNC(=O)C(=NOC)c1ccccc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C(=NOC)c1ccccc1CBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
Carbon tetrabromide (0.33 g) was added to a solution of N-methyl-2-(2-hydroxymethylphenyl)-2-methoxyiminoacetamide (0.11 g) and triphenylphosphine (0.26 g) in tetrahydrofuran (10 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1½ hours and then at room temperature for 1 hour. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The combined extracts were washed with brine and dried over magnesium sulphate. The solution was then concentrated under reduced pressure to leave a gum. Column chromatography (eluting with diethyl ether on silica gel) gave the N-methyl-2-(2-bromomethylphenyl)-2-methoxyimino-acetamide as a gum (80 mg, 57%). 1H NMR (CDCl3) δ2.95(d,3H), 4.0(s,3H), 4.35(s,2H), 6.8(brs,1H), 7.1-7.5(m,4H) ppm.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)=O.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]>CN(C)C=O.C(OCC)(=O)C>[CH3:24][O:23][C:21]([C:20]1[CH2:19][N:10]2[CH:9]=[CH:8][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([CH:1]=1)[C:11]2=3)=[O:22]
Reactant: COC(=O)CCBr
Reactant: O=Cc1cccc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1=Cc2cccc3ccn(c23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
To a solution of 7-formylindole (30 g, 0.206 mol) in dimethylformamide (930 mL) was added cesium carbonate (148.2 g, 0.454 mol) and the mixture was stirred vigorously at room temperature for 30 min. Methyl 3-bromopropionate (51.6 g, 0.308 mol) was added and the reaction mixture was heated to 80° C. for 24 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and filtered through a pad of Celite. The filtrate was washed with water and saturated aqueous sodium chloride, and the aqueous layers were back extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was passed through a short silica plug and concentrated under reduced pressure. Recrystallization of the crude product from chloroform and hexanes gave 4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester (17 g, 38.7% yield). Chromatography of the mother liquor gave additional 4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester (1.27 g, 2.9% yield) and 6H-Pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester (0.51 g, 1.2% yield).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:7]=1[CH:8]=[O:9])([CH3:4])[CH3:3].[OH:15]P([O-])(O)=O.[K+].[Mn]([O-])(=O)(=O)=O.[K+]>C(O)(C)(C)C>[CH3:4][C:2]([O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:7]=1[C:8]([OH:15])=[O:9])([CH3:1])[CH3:3]
Reactant: O=P([O-])(O)O
Reactant: CC(C)(C)Oc1cccc(Cl)c1C=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)Oc1cccc(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of 2-[(1,1-dimethylethyl)oxy]-6-chlorobenzaldehyde (8.40 g, 40.0 mmol) in t-butanol (200 mL) was added 1.25M KH2PO4 (pH 7, 200 mL) and 0.4M aqueous potassium permanganate (200 mL, 80 mmol). The reaction was stirred at room temperature for 3 h and was quenched by the addition of saturated aqueous sodium sulfite (200 mL). The brown suspension was acidified with 2N HCl with ice-cooling until the MnO2 dissolved (pH 4). The reaction was extracted with ethyl acetate (3 times) and the organic layers were washed with brine, dried (MgSO4) and concentrated to a white solid. The crude product was recrystallized from hexanes at 0° C. to afford 7.14 g (78%) of 2-[(1,1-dimethylethyl)oxy]-6-chlorobenzoic acid as white crystals: mp 117°-119° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.O[CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]1>>[O:11]=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][CH2:43][CH2:44][N:45]3[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:55])([CH3:57])[CH3:56])=[O:52])[CH2:47][CH2:46]3)[CH:10]=2)[C:6]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:7]1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: O=C1C(c2cccnc2)=C(c2ccccc2)c2ccc(O)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(c2cccnc2)=C3c2ccccc2)CC1
Reaction time: 19 h
Yield: 51 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 6-hydroxy-3-phenyl-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, t-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate instead of 4-(2-hydroxyethyl)morpholine, being stirred for 19 h, and being recrystallized with EtOAc to give the title compound (51%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([NH:16][NH2:17])=[O:15])=[CH:4][CH:3]=1.[C:18]1([CH2:24][C:25](Cl)=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:24]([C:25]1[O:15][C:14]([C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[N:16][N:17]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)NN
Reactant: O=C(Cl)Cc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1-c1nnc(Cc2ccccc2)o1

Procedure:
Prepared according to the procedure described in Example 8, Step 6, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid hydrazide and phenylacetyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.N(OC(C)(C)C)=O.[Si]([N:22]=[N+:23]=[N-])(C)(C)C>>[N:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N+:22]=[N-:23]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Nc1ccccc1
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: [N-]=[N+]=Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
A solution of aniline (500 mgs, 5.37 mmol) in acetonitrile (10 mL, 191 mmol) was cooled down in an ice bath and treated with tert-butyl nitrite (680 mgs, 6.59 mmol) and dropwise with TMS-N3 (0.713 mL, 5.37 mmol). The ice bath was removed and the mixture was stirred overnight at r.t. under N2. Acetonitrile was carefully evaporated (NB: azidobenzene is also volatile) and the residue (750 mgs) was passed through a silica gel pad (20 g) and eluted with petroleum ether (35-55° C.). Evaporation of the solvent gave the title material as an oil (500 mgs, 4.20 mmol, 78% yield) that still contains some traces of solvent as shown by 1H NMR. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.32-7.41 (m, 2H), 7.12-7.19 (m, 1H), 7.01-7.09 (m, 2H).
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH2:6][CH2:5]1>O>[CH3:2][NH:3][C:4]1([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:7](=[O:8])[CH2:6][CH2:5]1
Reactant: CNC1(c2cccs2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Product: CNC1(c2cccs2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of conc. HCl (15 ml) and water (8 ml) was added to N-methyl-8-(thiophen-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine (2 g, 7.9 mmole) and stirred for 5 days at RT. The reaction mixture was worked up by dilution with water (30 ml) and extraction with ether. The ethereal phase was discarded. The aqueous phase was then made alkaline with 2N NaOH and extracted with dichloromethane (3×30 ml). The organic phase thereby obtained was dried over Na2SO4 and then concentrated by evaporation on a rotary evaporator. The residue was purified by column chromatography (silica gel 60 (50 g); 500 ml ethyl acetate/ethanol (5:1)] and Ket-4 was obtained in a yield of 1.4 g (85%) as a solid with a melting point of 72°-74° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([C:24]2[N:25]=[CH:26][NH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+].CNC1CCCCC1NC>CN(C=O)C.[Cu]I>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([N:27]2[CH:28]=[C:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:25]=[CH:26]2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: Cn1cc(Br)cc(OCc2ccccc2)c1=O
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cn1cc(-n2cnc(-c3ccccc3)c2)cc(OCc2ccccc2)c1=O
Temperature: 110 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
3-(Benzyloxy)-5-bromo-1-methylpyridin-2(1H)-one (50 mg, 0.170 mmol), 4-phenylimidazole (29 mg, 0.201 mmol), Cs2CO3 (111 mg, 0.340 mmol), CuI (2 mg, 10.50 μmol), and N,N′-dimethyl-1,2-cyclohexanediamine (6 μl, 0.038 mmol) were combined in DMF (0.5 mL) in a screw cap vial. The vial was sealed then heated to 110° C. After stirring overnight the mixture was cooled to RT. CuI (2 mg) and N,N′-dimethyl-1,2-cyclohexanediamine (6 uL) were added and heating continued at 110° C. After 6 h the mixture was cooled to RT. The mixture was filtered using a 0.45 μm PTFE syringe filter then purified by preparative reversed-phase HPLC (20×150 mm Waters Sunfire (0.1% TFA), 5-50% CH3CN/water over 20 min at 20 mL/min). Fractions containing the product were pooled then passed through Dowex 1×2-400 ion exchange resin (prewashed with 1M NaOH, H2O, MeOH) washing with MeOH. The filtrate was concentrated to give the title compound (32 mg, 53%) as an amber film. 1H NMR (500 MHz, CDCl3): δ 7.78 (d, J=7.7 Hz, 2 H); 7.59 (s, 1 H); 7.45-7.36 (m, 9 H); 7.13 (d, J=2.5 Hz, 1 H); 6.73 (d, J=2.5 Hz, 1 H); 5.19 (s, 2 H); 3.65 (s, 3 H). LC/MS (M+H)+ 358.