Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:25](O)=[O:26])[C:12]2[C:17]([CH3:18])=[N:16][N:15]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[C:13]=2[N:14]=1.F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC.[C:42]([N:49]1[CH2:54][CH2:53][NH:52][C:51]([CH3:56])([CH3:55])[CH2:50]1)([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>ClCCl.C(N(CC)C(C)C)(C)C>[C:45]([O:44][C:42]([N:49]1[CH2:54][CH2:53][N:52]([C:25]([C:11]2[C:12]3[C:17]([CH3:18])=[N:16][N:15]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[C:13]=3[N:14]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=3[F:1])[CH:10]=2)=[O:26])[C:51]([CH3:56])([CH3:55])[CH2:50]1)=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3F)cc(C(=O)O)c12
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Agent: CC[n+]1ccccc1Br
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3F)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3(C)C)c12
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
To a suspension of 6-(2-fluoro-4-Hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (150 mg) in dry dichloromethane (3 mL), N,N-diisopropylethylamine (70 μL), 2-bromo-1-ethylpyridinium tetrafluoroborate (221 mg) and 1-Boc-3,3-dimethylpiperazine (87 mg) were added. The solution was stirred for 30 min. Upon complete conversion, the solution is evaporated in vacuo and 3 mL of 30% sodium methoxide in methanol were added. The mixture was stirred for 30 min, the pH was adjusted to 5 by addition of 2M hydrochloric acid. Ethyl acetate was added and the organic layer was extracted with saturated sodium bicarbonate, 20% aqueous ammonium chloride solution and multiple times with water. The organic layer was dried over sodium sulfate and evaporated to dryness to give 132 mg (58%) of the title compound.
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[C:32]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)=O.C(OP([CH2:53][C:54]#[N:55])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>CCCCCC>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)=[CH:53][C:54]#[N:55])[CH:40]=[CH:41][C:42]=1[O:43][CH3:44]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(C(=O)c2ccncc2)cc1OC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Product: COc1ccc(C(=CC#N)c2ccncc2)cc1OC

Procedure:
3-(3,4-Dimethoxyphenyl)-3-pyridin-4-ylacrylonitrile was prepared analogously to methyl 3,3-bis-(3′,4′-dimethoxyphenyl)acrylate using 4-(3,4-dimethoxybenzoyl)pyridine (1 g,4 mmol), diethylcyanomethylphosphonate (0.73 mL, 4.4 mmol) and lithium hexamethyldisilazide (3.4 mL, 4.4 mmol, 1.3 M) with a reaction time of 24 hours at room temperature. The crude product was slurried in 10 mL of hexane. The mixture was filtered, the solid was washed with hexane, air dried and then dried in vacuo to afford 0.91 g (85%) of a mixture of the E and Z isomers as an off white solid: mp 116-125° C.; 1H NMR (CDCl3) δ 8.80-8.63 (m, 4 H), 7.40-7.20 (m, 4 H), 7.04-6.74 (m, 6 H), 5.81 (s, 1 H), 5.70 (s, 1 H), 3.94 (s, 3 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 3.84 (s, 3 H); 13C NMR (CDCl3) δ 160.1, 157.0, 151.6, 151.1, 150.3, 149.2, 148.9, 146.7, 144.9, 129.6, 127.8, 123.7, 123.1, 122.7, 122.1, 117.4, 117.1, 112.3, 111.0, 110.5, 96.1, 94.8, 56.0, 56.0; Anal. Calcd for C16H14N2O2. Theoretical: C, 72.17; H, 5.30; N, 10.52. Found: C, 72.35; H, 5.43; N, 10.47.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:12][CH:11]=1)[CH3:2].[CH2:29]([I:31])[CH3:30].[CH2:32](O)[CH3:33]>>[I-:31].[I-:31].[CH2:25]([N+:22]([CH2:29][CH3:30])([CH2:23][CH3:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N+:3]([CH2:32][CH3:33])([CH2:1][CH3:2])[CH2:27][CH3:28])=[CH:15][CH:14]=1)[CH3:26]
Reactant: CCI
Reactant: CCN(CC)CCCCCCc1ccc(CCCCCCN(CC)CC)cc1
Reactant: CCO
Product: CC[N+](CC)(CC)CCCCCCc1ccc(CCCCCC[N+](CC)(CC)CC)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
First, 300 mg of 1,4-bis(6-diethylaminohexyl)benzene were dissolved in 3 ml of absolute ethanol, and after adding 616 μl of ethyl iodide, the mixture was stirred at a room temperature for 30 minutes, refluxed for 1.5 hours, and then cooled. The mixture was evaporated under a reduced pressure, and after adding 3 ml of acetone, evaporated under a reduced pressure. The residue was dissolved in 1.5 ml of acetone, and the solution was allowed to stand in a freezer for 2 days. The resulting crystal was collected by filtration, washed with ethyl acetate and dried under a reduced pressure to obtain 490 mg of the title compound as a colorless crystal.
Reaction SMILES: [CH:1]([P:3](=[O:17])([CH:15]=[CH2:16])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=1)=[CH2:2].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:18]([N:25]1[CH2:16][CH2:15][P:3](=[O:17])([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=2)[CH2:1][CH2:2]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: C=CP(=O)(C=C)c1ccc([N+](=O)[O-])c(OC)c1
Solvent: C1CCOC1
Product: COc1cc(P2(=O)CCN(Cc3ccccc3)CC2)ccc1[N+](=O)[O-]
Temperature: 105 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.480 g, 1.90 mmol) and benzylamine (0.23 mL, 2.08 mmol) were dissolved in 50% aqueous THF (6 mL) and heated to 105° C. under nitrogen. After one hour, another portion of benzylamine was added to the reaction mixture. The reaction mixture was refluxed for an additional 2 h, and then cooled to rt. The reaction mixture was partitioned between saturated aqueous NaHCO3 and CH2Cl2. The aqueous phase was washed once with CH2Cl2 and the organic layers were combined. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-5% 7N ammonia in methanol:dichloromethane) to afford the desired product (0.449 g, 66% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N+:11]([O-])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:29][C@H:28]4[N:24]([CH2:25][CH2:26][CH2:27]4)[C:23]4[N:30]=[C:31]([NH:34][CH2:35][CH3:36])[N:32]=[CH:33][C:22]=4[C:21]3=[O:37])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([N:20]3[CH2:29][C@H:28]4[N:24]([CH2:25][CH2:26][CH2:27]4)[C:23]4[N:30]=[C:31]([NH:34][CH2:35][CH3:36])[N:32]=[CH:33][C:22]=4[C:21]3=[O:37])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc([N+]3([O-])CCN(C(=O)OC(C)(C)C)CC3)c1)C2=O
Agent: [Pd]
Solvent: CCO
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(N3CCN(C(=O)OC(C)(C)C)CC3)c1)C2=O
Yield: 71.8 %

Procedure:
(S)-4-Tert-butoxycarbonyl-1-[3-(9-ethylamino-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]piperazine-1-oxide (0.338 g, 0.645 mmol) obtained in Step 2 was dissolved in ethanol (10 mL), and the mixture was stirred for 1.5 hours under a stream of hydrogen gas after adding 10% palladium-on-carbon (137 mg, 0.0646 mmol). The mixture was filtered through sellite, and the filtrate was concentrated to give (S)-5-[3-(4-tert-butoxycarbonylpiperazine-1-yl)phenyl]-9-ethylamino-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (0.235 g, 72%).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][OH:20].C(=O)([O-])O.[K+]>O1CCCC1>[OH:20][CH2:19][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][CH:1]=[O:3]
Reactant: O=CO
Reactant: Nc1ccccc1CCO
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: O=CNc1ccccc1CCO
Temperature: 60 °C
Reaction time: 2 h

Procedure:
12.6 ml of formic acid were added dropwise at 0° C. to 15 ml of acetic anhydride, and the mixture was then stirred for 2 hours at 60° C. After cooling to 20° C., the mixture was diluted with 140 ml of tetrahydrofuran, cooled to −4° C., and at this temperature a solution of 18.4 g of 2-(2-aminophenyl)ethanol in 185 ml of tetrahydrofuran was added dropwise. After stirring for 3 hours at −6° C. the mixture was neutralised with aqueous potassium hydrogen carbonate solution (25% KHCO3) and extracted four times with 300 ml of ethyl acetate each time. The combined extracts were dried over sodium sulfate and concentrated by evaporation in vacuo. 18.4 g (94% of theory) of the title compound were thereby obtained in the form of yellowish crystals that melted at 49–54° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].C(N(CC)CC)C.[CH3:17][O:18][C:19](=[O:43])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[N:41][CH:40]=[CH:39][N:38]=3)=[CH:33][CH:32]=2)[CH:23]=1>>[CH3:17][O:18][C:19](=[O:43])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[N:41][CH:40]=[CH:39][N:38]=3)=[CH:33][CH:32]=2)[S:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)(=[O:8])=[O:7])[CH:23]=1
Reactant: O=S(=O)(Cl)c1nccs1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cnccn3)cc2)S(=O)(=O)c2nccs2)c1

Procedure:
The title compound of Step A was prepared following the method dissolved in Step A of Example 1 from 3-{3-[(4-pyrazin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11a, and thiazole-2-sulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.61 (s, 1H), 8.50 (s, 1H), 7.96 (d, 1H), 7.88 (d, 2H), 7.60 (d, 1H), 7.26 (d, 2H), 7.13 (m, 1H), 7.04 (m, 1H), 6.95 (m, 1H), 6.91 (s, 1H), 4.54 (s, 2H), 4.48 (s, 2H), 3.64 (s, 3H), 2.81 (t, 2H), 2.52 (t, 2H); MS 509 (M+1).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F-].[K+].I[C:40]1[S:41][CH:42]=[CH:43][CH:44]=1>C(OCC)C>[S:41]1[CH:42]=[CH:43][CH:44]=[C:40]1[C:3]#[C:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1
Reactant: Ic1cccs1
Reactant: C[Si](C)(C)C#Cc1cc2ccccc2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: C(#Cc1cc2ccccc2s1)c1cccs1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
The reaction mixture from Step A containing 2-trimethylsilylethynylbenzothiophene was stirred, and 4.96 grams (0.0157 mole) of tetrabutylammonium fluoride trihydrate and 10.1 grams (0.173 mole) of potassium fluoride were added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 4.5 hours. After this time 36.3 grams (0.173 mole) of 2-iodothiophene was added via syringe. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 60 hours. After this time the reaction mixture was dissolved in diethyl ether and a small amount of methylene chloride, and it was washed with two portions of an aqueous solution of 10% ammonium chloride, one portion of water and one portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished with hexane and 20% methylene chloride in hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 35.1 grams of 2-(thien-2-ylethynyl)benzothiophene.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][C:10]2[NH:9][C:8](=[S:12])[C:7]([C:13]#[N:14])=[CH:6][C:5]=2[C:4](=[O:15])[CH2:3]1.Br[CH2:18][CH2:19][CH3:20]>>[CH3:1][C:2]1([CH3:16])[CH2:11][C:10]2[N:9]=[C:8]([S:12][CH2:18][CH2:19][CH3:20])[C:7]([C:13]#[N:14])=[CH:6][C:5]=2[C:4](=[O:15])[CH2:3]1
Reactant: CCCBr
Reactant: CC1(C)CC(=O)c2cc(C#N)c(=S)[nH]c2C1
Product: CCCSc1nc2c(cc1C#N)C(=O)CC(C)(C)C2
Yield: 91 %

Procedure:
In analogy to the procedure described in Example 1, 7,7-dimethyl-5-oxo-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile was treated with 1-bromopropane to give the title compound in 91% yield.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:21]=[C:17]([C:18](O)=O)[C:16]([OH:22])=[CH:15][CH:14]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:18]([C:17]3[CH:21]=[C:13]([F:12])[CH:14]=[CH:15][C:16]=3[OH:22])=[N:9][C:7](=[O:8])[C:6]=2[CH:10]=1
Reactant: O=C(O)c1cc(F)ccc1O
Reactant: NC(=O)c1cc(F)ccc1O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1C
Solvent: c1ccncc1
Product: O=c1nc(-c2cc(F)ccc2O)oc2ccc(F)cc12
Reaction time: 1 h

Procedure:
4.3 g of 5-fluoro-salicylamide and 4.7 g of 5-fluorosalicylic acid are boiled under reflux in 50 ml of xylene after addition of 0.3 ml of pyridine. 4.4 ml of thionyl chloride are added in the course of 2 h, the mixture is stirred for a further 1 h and the solvent is then distilled off under reduced pressure. The residue is suspended in 30 ml of ethanol, filtered off and washed with ethanol. After drying, 6-fluoro-2-(5-fluoro-2-hydroxyphenyl)benz[e][1,3]oxazin-4-one is obtained as slightly yellow crystals of m.p. 250-252 C.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:4][CH:5]=[CH:6][CH:7]=[CH:8][C:9](Cl)=[O:10].[C:20]1([NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26].CN1CCOCC1>C(Cl)Cl>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:27][C:9](=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH2:4][CH:3]([O:2][CH3:1])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: Nc1ccccc1N
Reactant: COc1ccc(C(CC=CC=CC(=O)Cl)OC)cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(C(CC=CC=CC(=O)Nc2ccccc2N)OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.5 %

Procedure:
To a stirred solution of acid chloride 5 (115 mg,0.41 mmol) in CH2Cl2 (5 mL) at 0° C. was added 1,2-phenylenediamine (133 mg,1.23 mmol) followed by N-methylmorpholine (49 μL, 0.45 mmol). The mixture was stirred at 0° C. for 1 h, and then was allowed to warm to rt over 1 h. After being stirred for an additional 1 h at rt, the reaction mixture was partitioned between CHCl3 (2×15 mL) and water (15 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by flash silica gel chromatography (50% ethyl acetate in hexane) afforded the desired benzamide 18 (21 mg, 15% yield): 1H NMR (300 MHz, CDCl3) δ 6.65-7.40 (m, 9H), 5.96-6.20 (m, 2H), 5.92 (d, J=15.3 Hz, 1H), 4.18 (m, 1H), 3.82 (br s, 2H), 3.81 (s, 3H ), 3.19 (s, 3H), 2.61 (m, 1H), 2.43 (m, 1H); 13CNMR (75.4 MHz,CDCl3) δ 41.7, 55.2, 56.4, 82.7, 113.8, 118.2, 119.5, 121.8, 124.4, 125.0, 127.0, 127.8, 130.1, 133.1, 139.5, 140.7, 142.4, 159.2, 164.6.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.[H-].[Na+].[Cl:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([OH:25])=[O:24]>CN(C)C=O>[ClH:18].[NH2:1][CH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([OH:25])=[O:24]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: O=C(O)c1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cl
Product: NCc1cccc(C(=O)O)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
4.34 g (20.0 mmol) of di(t-butyl) iminodicarboxylate was added to a mixture of 800 mg (20.0 mmol) of sodium hydride (60% dispersion in mineral oil) and 50 ml of dimethylformamide. 1.71 g (10.0 mmol) of 3-chloromethylbenzoic acid was added to the obtained mixture, and they were stirred at 80° C. for 2 hours. After the concentration under reduced pressure, 40 ml of dioxane containing 4 M of hydrogen chloride was added to the residue, and they were stirred at room temperature overnight. A white precipitate thus formed was taken by the filtration and washed with ethyl acetate to obtain 3-aminomethylbenzoic acid hydrochloride as white crystals. A mixture of this aminomethyl compound, 10 ml of water, 10 ml of 28% aqueous ammonia and 3.00 g (71.4 mmol) of cyanamide was stirred at 60° C. for 7 days. The solvent was evaporated, and the residue was purified by the reversed-phase HPLC in the same manner as that in step 5 in Example 1 to obtain the title compound.
Reaction SMILES: C([Li])(CC)C.C(O[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=C(OC)C=1C)=O)(C)(C)C.C1([C:26](CC2C(OC)=CC=CC=2NC(OC(C)(C)C)=O)=[O:27])CC1.C1C[O:48]CC1>C1CCCCC1>[CH3:26][O:27][N:13]([CH3:11])[C:14]([CH:19]1[CH2:18][CH2:17]1)=[O:48]
Reactant: C1CCOC1
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1CC(=O)C1CC1
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1C
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Product: CON(C)C(=O)C1CC1

Procedure:
Using the procedure described in Example 9, Part A, 100 mL (130 mmol) of 1.3M sec-butyl lithium in cyclohexane was reacted with N-tert-butoxycarbonyl-3-methoxy-2-methylaniline (15.4 g, 65 mmol) in 100 mL of THF and then with 8.4 g (65 mmol) of N-methoxy-N-methylcyclopropylcarboxamide to give crude [2-(tert-butoxycarbonylamino)-6-methoxyphenyl]methyl cyclopropyl ketone. This material on treatment with 20 mL of trifluoroacetic acid in 300 mL of methylene chloride for 6 hours gave a material that was chromatographed on silica gel. Eluting with a gradient, toluene→5% EtOAc/toluene, there was obtained 6.4 g (52% yield) of 2-cyclopropyl-4-methoxy-1H-indole as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH:17]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:18][C:19]([OH:21])=[O:20])[C:13](=[O:28])[C:12]2=[O:29])=[CH:5][CH:4]=1)#[N:2].S(Cl)(Cl)=O.[CH2:36](O)[CH3:37]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH:17]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:18][C:19]([O:21][CH2:36][CH3:37])=[O:20])[C:13](=[O:28])[C:12]2=[O:29])=[CH:30][CH:31]=1)#[N:2]
Reactant: N#Cc1ccc(OCCCN2CCN(C(CC(=O)O)c3cccnc3)C(=O)C2=O)cc1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CC(c1cccnc1)N1CCN(CCCOc2ccc(C#N)cc2)C(=O)C1=O

Procedure:
In 14 ml of ethanol was suspended 0.70 g of (-)-3-[4-[3-(4-cyanophenoxy)propyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)propionic acid, followed by adding thereto 0.15 ml of thionyl chloride under ice-cooling, and the resulting mixture was heated under reflux for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure and 10 ml of ethyl acetate and 10 ml of water were added to the resulting residue, and the pH was adjusted to 7.5 with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure to obtain 0.5 g of ethyl (-)-3-[4-[3-(4-cyanophenoxy)propyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)propionate as colorless crystals having a melting point of 110.5-112° C.
Reaction SMILES: C(Cl)(Cl)Cl.CCCCCC.C1CO[C:13]2([C:19]3[CH:20]=[CH:21][C:22]([CH2:24][C:25]([OH:27])=[O:26])=[CH:23][C:18]=3[CH:17]=[CH:16][C:15]3[CH:28]=[CH:29][CH:30]=[CH:31][C:14]2=3)[O:12]1>CC(C)=O.CCCCCC>[CH:23]1[C:18]2[CH:17]=[CH:16][C:15]3[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=3[C:13](=[O:12])[C:19]=2[CH:20]=[CH:21][C:22]=1[CH2:24][C:25]([OH:27])=[O:26]
Reactant: O=C(O)Cc1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: CCCCCC
Product: O=C(O)Cc1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
2.0 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid is dissolved in 20 ml. of acetone and to the solution is added 20 ml. of N-hydrochloric acid. The mixture is refluxed for 1 hour, then cooled, diluted with water, and extracted with ethyl acetate. The extract is washed, dried and evaporated to give a 90% yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid, m.p. (chloroform-hexane) 138°-139° C.; m.p. (acetone-hexane) 113°-115° C. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetic acid gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid, m.p. (acetone-hexane) 148°-149.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].N#N.[OH2:26]>N1C=CC=CC=1>[C:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]=[N:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][C:17](=[O:26])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:7][CH:6]=2)=[CH:11][CH:12]=1)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: Oc1ccc(N=Nc2ccc(O)cc2)cc1
Reactant: CC(C)(C)C(=O)Cl
Reactant: O
Agent: N#N
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc(N=Nc2ccc(OC(=O)C(C)(C)C)cc2)cc1

Procedure:
1 g (0.0047 mole) of 4,4'-dihydroxyazobenzene and 2 g (0.016 mole) of pivaloyl chloride was stirred in 20 mls of pyridine for 24 hrs. at room temperature. The solvent was blown off under a stream of N2. Water was added and the crude product filtered and recrystallized from ethanol; 1.5 g (83%) yield. M.P.~185°-188° C.
Reaction SMILES: [NH2:1][OH:2].[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[CH2:16][O:15][CH2:14][CH2:13][N:12]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:7][CH:6]=1)=O>C(O)C>[OH:2][N:1]=[CH:3][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[CH2:16][O:15][CH2:14][CH2:13][N:12]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1c1ccc(C=O)cc1
Reactant: NO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1c1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
Hydroxylamine (2.513 mL of 50% w/v, 38.04 mmol) was added to a stirred solution of tert-butyl (3R)-3-(4-formylphenyl)morpholine-4-carboxylate 11 (5.54 g, 19.02 mmol) in ethanol (29.66 mL) and the resulting mixture stirred at rt for 1 h. The reaction mixture was concentrated in vacuo and then redissolved in EtOAc (50 mL) and sequentially washed with water (2×20 mL) and brine (1×20 mL), dried over MgSO4, filtered and concentrated in vacuo to leave product as a white foam (5.57 g, 96% yield); 1H NMR (400.0 MHz, DMSO) d 1.39 (9H, s), 3.08 (1H, m), 3.49 (1H, m), 3.69-3.83 (4H, m), 4.28 (1H, m), 4.98 (1H, s), 7.36 (2H, m), 7.58 (2H, m), 8.13 (1H, s) and 11.23 (1H, s) ppm.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[NH:17][N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:24]([O-])([O-])=O.[Cs+].[Cs+].CI.O>CN(C=O)C>[CH3:24][N:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[N:16]1
Reactant: O=C([O-])[O-]
Reactant: c1ccc(COc2ccc(-c3n[nH]c4cccnc34)cc2)cc1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2ccc(O)cc2)c2ncccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.4 %

Procedure:
To a stirred mixture of 3-[4-(benzyloxy)phenyl]-1H-pyrazolo[4,3-b]pyridine (300 mg) and Cs2CO3 (649 mg) in DMF (4 mL) was added MeI (0.093 mL) at 0° C. The mixture was stirred at room temperature for 12 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in EtOH (20 mL) and 10% Pd—C (50% wet, 200 mg) was added. The mixture was stirred for 1 h under H2 atmosphere, filtered and evaporated. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (160 mg).