Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:23].[K+]>O>[I:23][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [I-]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])cc1I
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a solution of 2-amino-4-nitrobenzoic acid (14.5 g, 79.6 mmol) in 2.0 M of sulfuric acid aqueous solution (398 mL, 796 mmol) was added a solution of sodium nitrite (8.24 g, 0.119 mol) in water dropwise at 0° C. After the addition, the resulting solution was stirred at same temperature for 1 hour, then a solution of potassium iodide (19.8 g, 0.119 mol) in water was added dropwise at 0° C. The resulting mixture was stirred at rt for 72 hours. The precipitate was filtered and washed by water to give the desired product (19.5 g, 83%). LCMS calculated for C7H51NO4(M+H)+: m/z=294.0.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8]2[CH:11]=[CH:12][C:3]=1[CH:4](Br)[O:5][CH2:6][O:7]2.[C-:14]#[N:15].[K+].O>C(O)C>[F:1][C:2]1[C:9]([F:10])=[C:8]2[CH:11]=[CH:12][C:3]=1[CH:4]([C:14]#[N:15])[O:5][CH2:6][O:7]2
Reactant: Fc1c2ccc(c1F)C(Br)OCO2
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CC1OCOc2ccc1c(F)c2F
Temperature: 70 °C
Reaction time: 5 h
Yield: 95.2 %

Procedure:
2,3-Difluoromethylenedioxybenzyl bromide (40.4 g) was dissolved in ethanol and potassium cyanide (11.3 g) was added. The mixture was stirred at 70° C. for 5 hours. Water and a further portion of potassium cyanide (2 g) were added and the mixture was stirred at 70° C. for a further 3 hours. Most of the solvent was removed in vacuo and water was added to the residue, which was extracted with diethyl ether, washed with water, dried and concentrated to yield the title compound as a yellow oil, (30.2 g), NMR (CDCl3): 3.80(s,2H), 7.10(m,3H).
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].O[N:28]1[C:33](=[O:34])[CH2:32][CH2:31][C:29]1=[O:30].C1CCC(N=C=NC2CCCCC2)CC1.C1CCC(NC2CCCCC2)CC1>C1COCC1.C(OCC)(=O)C>[NH:1]([C:10]([O:12][CH2:13][CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[C:26]1=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:11])[C@H:2]([C:7]([O:9][N:28]1[C:33](=[O:34])[CH2:32][CH2:31][C:29]1=[O:30])=[O:8])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: O=C1CCC(=O)N1O
Reactant: CSCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Fmoc-Met-OSu was prepared in situ by the reaction of Fmoc-Met-OH (14.87 g), HOSu (5.52 g) and DCC (8.26 g) in THF (tetrahydrofuran, 200 ml) at 0° C. for 3.5 hours. Precipitated dicyclohexylurea (DCU) was removed by filtration and the THF filtrate was added to a cold solution of H-Asp(OtBu)-OH in 220 ml of 10:1 water/THF to which had been added 40 ml of 1N sodium hydroxide. After stirring the reaction mixture at room temperature overnight, solid citric acid (20 g) was added along with ethyl acetate (600 ml). The ethyl acetate layer was separated, washed with 10% citric acid and brine, then dried (MgSO4). Evaporation of the ethyl acetate solution gave a residue which was dissolved in ethyl acetate (200 ml) and treated with DCHA (7.84 ml) to precipitate 17.93 g of the DCHA salt of the title compound, mp 159°-162° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8][CH2:7]1)[CH3:2].Cl[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([NH:12][C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:11]1)[CH3:2]
Reactant: Clc1ncccn1
Reactant: CCOC(=O)C[C@H]1CC[C@H](N)CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C[C@H]1CC[C@H](Nc2ncccn2)CC1

Procedure:
A solution of trans-(4-Amino-cyclohexyl)-acetic acid ethyl ester (Karapavicius K., Palaima A. I., Knunyants I. L., Izv. Akad. Nauk SSSR, Ser. Khim., 1980;10;2374-9) (3.46 g, 18.7 mmol), 2-chloropyrimidine (2.14 g, 18.7 mmol) and triethylamine (5.21 mL) is refluxed in ethanol (EtOH) (10 mL) for 48 hours. The reaction is cooled, and the solvents are removed under reduced pressure. The residue is partitioned between chloroform and 2N aqueous sodium carbonate solution. The organic layer is separated, dried over sodium sulfate, and the solvents are removed under reduced pressure. The residue is chromatographed over silica gel using a mixture of chloroform and methanol to give trans-[4-(pyrimidin-2-ylamino)-cyclohexyl]-acetic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[CH:10]1[C:18]2[C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15][C:14]=2[C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:22]1[C:16]2[S:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:18]=3[C:17]=2[CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccccc1Br
Reactant: OB(O)c1cccc2c1sc1ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1cccc2c1sc1ccccc12
Temperature: 25 °C

Procedure:
2-Bromoanisole (5.61 g, 30 mmol) and 4-dibenzothiopheneboronic acid (6.84 g, 30 mmol), Pd2(PPh3)4 (1.00 g, 0.8 mmol) were dissolved in 100 ml of toluene. Saturated solution of sodium carbonate (12.5 g in water) was added, and reaction mixture was heated to reflux under N2 atmosphere overnight. Then reaction mixture was cooled down to room temperature, separated organic phase and evaporated toluene. The solid residue was subjected to column chromatography on silica (eluent—hexane/ethyl acetate 4/1) providing 4-(2-methoxyphenyl)dibenzo[b,d]thiophene as 6.6 g of colorless solidified oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[C:10]([CH3:12])[CH3:11])[CH:6]=[CH:5][C:4]=1[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17]>[Pd]>[CH2:9]([C:7]1[CH:6]=[CH:5][C:4]([CH:13]([OH:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:8]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: CCCCC(=O)c1ccc(C=C(C)C)cc1OC
Agent: [Pd]
Product: CCCCC(O)c1ccc(CC(C)C)cc1OC
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
A mixture of 2'-methoxy-4'-(2-methyl-1-propenyl)valerophenone (88 mg) and 10% palladium on carbon (30 mg) was stirred under hydrogen atmosphere for 30 minutes. Catalyst was removed by filtration and the filtrate was concentrated. The residue was dissolved in methanol (5 ml) and then sodium borohydride (16 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. The mixture was poured into ice water and acidified with 6N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated to give 1-(4-isobutyl-2-methoxyphenyl)pentanol (88 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=1)=[O:19]
Reactant: O=C(CBr)c1cc(-c2ccccc2)no1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2cc(-c3ccccc3)no2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 5-(bromoacetyl)-3-phenylisoxazole. 1H-NMR (CDCl3) δ: 8.27 (1H, d, J=1.8 Hz), 7.89-7.84 (2H, m), 7.56-7.47 (5H, m), 7.30 (1H, dd, J=1.8, 8.4 Hz), 6.18 (2H, s), 4.13 (2H, q, J=7.2 Hz), 1.10 (3H, t, J=7.2 Hz)
Reaction SMILES: [O:1]=[C:2]1[O:6][CH2:5][N:4]([C:7]([O:9][CH2:10][CH:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:8])[C@H:3]1[CH2:24][O:25][C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.N#N>C(Cl)(Cl)Cl.CCOC(C)=O>[CH:22]1[C:23]2[CH:11]([CH2:10][O:9][C:7]([N:4]([CH3:5])[C@@H:3]([CH2:24][O:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[C:2]([OH:6])=[O:1])=[O:8])[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cccc(OC[C@H]2C(=O)OCN2C(=O)OCC2c3ccccc3-c3ccccc32)c1
Agent: CC[SiH](CC)CC
Agent: N#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cccc(OC[C@@H](C(=O)O)N(C)C(=O)OCC2c3ccccc3-c3ccccc32)c1
Yield: 61.1 %

Procedure:
(S)-(9H-fluoren-9-yl)methyl 5-oxo-4-((m-tolyloxy)methyl)oxazolidine-3-carboxylate (825 mg, 1.921 mmol) was dissolved in CHCl3 (10 mL) and added triethylsilane (1.534 ml, 9.60 mmol) followed by TFA (10 ml, 130 mmol) and stirred at RT under positive pressure of N2 for 18 hrs. The reaction was then evaporated on rotovap until a sticky oil was left behind. The oil was dissolved in EtOAc and then extracted with sat. sodium bicarbonate (10 ml×2). There was a middle layer between the aqueous layer and organic layer that appeared to be the deprotonated product. The aqueous layer and middle layer were separated and collected and then acidified until pH 4-5. The solution formed a precipitate once acidic. EtOAc (200 ml) was used to extract the precipitate. The organic layer washed with brine, collected, dried over MgSO4, filtered and evaporated to get the pure product (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(m-tolyloxy)propanoic acid (506 mg, 1.173 mmol, 61.0% yield) as a white solid. ESI-MS (+) m/z=454 (M+Na)
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.C([BH3-])#N.[Na+].[F:15][C:16]1[C:17]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=2[F:40])=[C:18]([CH:26]=[C:27]([CH:30]=O)[C:28]=1[F:29])[C:19]([NH:21][O:22][CH2:23][CH2:24][OH:25])=[O:20]>O1CCCC1>[F:15][C:16]1[C:17]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=2[F:40])=[C:18]([CH:26]=[C:27]([CH2:30][N:2]2[CH2:3][CH2:4][CH2:5][CH2:6][C:7]2=[O:9])[C:28]=1[F:29])[C:19]([NH:21][O:22][CH2:23][CH2:24][OH:25])=[O:20]
Reactant: COC(=O)CCCCN
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NOCCO)c1cc(CN2CCCCC2=O)c(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37 %

Procedure:
Methyl 5-amino-pentanoate hydrochloride {see J. Org. Chem. (1968) 1581} (128 mg, 0.178 mmol) and sodium cyanoborohydride (45 mg, 0.718 mmol) were added to a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (115 mg, 0.239 mmol) obtained in Step F of Example 1 in tetrahydrofuran (anhydrous, 4.0 mL). The mixture was stirred at room temperature for 1.5 hours. Then, the reaction vessel was equipped with a reflux condenser, and the mixture was heated at 60° C. for 2 days. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography (Mega Bond Elut, Varian, 4% methanol/methylene chloride as an eluent) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-piperidin-1-ylmethyl)-benzamide (Compound H-4, 42.7 mg, 37%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(OC([N:26]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:27]1)=O)(C)(C)C.[ClH:37]>>[ClH:37].[CH3:18][O:17][C:6]1[C:5]2[C:9](=[CH:10][C:2]([N:34]3[CH2:33][CH2:32][N:31]([CH:28]4[CH2:29][CH2:30][NH:26][CH2:27]4)[CH2:36][CH2:35]3)=[CH:3][CH:4]=2)[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: COc1nn(-c2ccccc2)c2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCNCC2)C1
Agent: Cl
Product: COc1nn(-c2ccccc2)c2cc(N3CCN(C4CCNC4)CC3)ccc12

Procedure:
The title compound was prepared according to the procedure as described in Example 57 reacting 6-bromo-3-methoxy-1-phenyl-1H-indazole and 3-piperazin-1-yl-pyrrolidine-1-carboxylic acid tert-butyl ester, followed by de-protection with HCl.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C@@:10]23[CH2:25][C@H:24]2[CH2:23][C:22]([F:27])([F:26])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]([NH:28]C(=O)OC(C)(C)C)[C:15](=[O:36])[N:14]2[CH2:37][C@H:38]([O:40][C:41]4[N:42]=[C:43]5[C:48](=[C:49]6[C:54]=4[CH:53]=[CH:52][CH:51]=[CH:50]6)[CH:47]=[CH:46][CH:45]=[CH:44]5)[CH2:39][C@H:13]2[C:12](=[O:55])[NH:11]3)=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[ClH:56]>C(OCC)(=O)C.O1CCOCC1>[NH2:28][C@@H:16]1[C:15](=[O:36])[N:14]2[CH2:37][C@H:38]([O:40][C:41]3[N:42]=[C:43]4[C:48](=[C:49]5[C:54]=3[CH:53]=[CH:52][CH:51]=[CH:50]5)[CH:47]=[CH:46][CH:45]=[CH:44]4)[CH2:39][C@H:13]2[C:12](=[O:55])[NH:11][C@:10]2([C:8]([NH:7][S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[O:9])[CH2:25][C@H:24]2[CH2:23][C:22]([F:26])([F:27])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[ClH:56]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4c4ccccc34)CN2C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4c4ccccc34)CN2C1=O
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (2R,6S,13aS,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-12,12-difluoro-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate (Example 19, 195 mg, 0.249 mmol) in ethyl acetate (1 mL) stiffing at room temperature was added 4 N hydrogen chloride (1.24 mL, 5.0 mmol) in dioxane. The reaction mixture was stirred for 4 h, and then the solvent was evaporated under reduced pressure. The residue was triturated with ethyl acetate and the product was filtered as a white solid. The solid was dissolved in methanol and the solvent was evaporated to provide the title compound (2R,6S,13aS,14aR,16aS)-6-amino-N-(cyclopropylsulfonyl)-12,12-difluoro-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide, Hydrochloric Acid (178 mg, 0.247 mmol, 99% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH3:15])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)=[O:5])[CH3:2].[C:20]([O:24][C:25]([N:27]1[CH2:31][C@H:30]([CH3:32])OS1(=O)=O)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:30]([CH3:32])[CH2:31][NH:27][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH3:15])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(C)c(C(F)(F)F)cc2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: CCOC(=O)c1cc2cc(C)c(C(F)(F)F)cc2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, m.p.: 103–105° C., EI-MS: m/e=428.1 (M+) and αD20=−40.3, was prepared in accordance with the general method of example 12b) from 5-methyl-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH:9]=[CH:8][C:7]([C:11]([OH:13])=O)=[CH:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.COC(Cl)=O.[CH2:26]([NH2:29])[CH2:27][CH3:28]>ClCCl>[CH2:26]([NH:29][C:11]([C:7]1[CH:8]=[CH:9][CH2:10][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=1)=[O:13])[CH2:27][CH3:28]
Reactant: CCCN
Reactant: CC(=O)NC1C=C(C(=O)O)C=CC1
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCNC(=O)C1=CC(NC(C)=O)CC=C1

Procedure:
A solution of 180 mg (1 m mole) of 3-acetamido-1,5-cyclohexadiene carboxylic acid in 5 ml of dichloromethane is treated with 202 mg (2 m mole) of triethylamine and 94 mg (1 m mole) of methylchloroformate. After 30 minutes at 25° C. the solution is treated with 60 mg (1 m mole) of n-propylamine for 1 hour at 25° C. after which the solution is diluted with dichloromethane and, washed with water, dried and evaporated to give N-propyl-3-acetamido-1,5-cyclohexadienecarboxamide.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)(=O)C>[N:14]1([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1
Reactant: c1ccc(CN2CCC(n3ccc4ccccc43)CC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: c1ccc2c(c1)ccn2C1CCNCC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A glacial acetic acid (15 mL) solution containing Pd(OH)2 /C and 1-benzyl-4-(1-indolyl)-piperidine was placed under an H2 atmosphere. The reaction temperature was raised to 80° C. After 1 hour, the reaction was cooled to room temperature and filtered. The filtrate was made basic (pH 8-9) with saturated NaHCO3, and extracted with methylene chloride. The extract was washed with water, dried, and concentrated. This material was sufficiently pure for further reactions giving 1.09 g (80% yield) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:13]1[C:14](=[O:28])[CH2:15][CH2:16][CH:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:18]=1[OH:19])(=O)[CH2:9][CH2:10][CH3:11].Cl.[CH2:30]([O:33][NH2:34])[CH:31]=[CH2:32]>C(O)C>[CH2:30]([O:33][N:34]=[C:8]([C:13]1[C:14](=[O:28])[CH2:15][CH2:16][CH:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:18]=1[OH:19])[CH2:9][CH2:10][CH3:11])[CH:31]=[CH2:32]
Reactant: C=CCON
Reactant: CCCC(=O)C1=C(O)C(c2ccc(OC)cc2)CCC1=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=CCON=C(CCC)C1=C(O)C(c2ccc(OC)cc2)CCC1=O
Reaction time: 8 h
Yield: 66.6 %

Procedure:
Triethylamine (1.2 g) was added to a solution of 2-butyryl-3-hydroxy-4-(4-methoxyphenyl)cyclohex-2-e-n-1-one (2.9 g) and O-allylhydroxylamine hydrochloride (1.2 g) in absolute ethanol (50 ml) at ambient temperature. After stirring overnight at this temperature, the ethanol was evaporated in vacuo, water was added to the residue and the aqueous solution was extracted with methylene chloride. The organic extracts were dried over anhydrous magnesium sulphate and then evaporated in vacuo. The residue was chromatographed on a silica gel column using 10% Et2O--CH2Cl2 as eluant to give the title compound (2.3 g) as a yellow oil.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][NH2:14])[CH2:8][CH2:7][CH2:6]2.[CH3:15][C:16]([CH3:18])=O.C([BH3-])#N.[Na+]>CO>[ClH:1].[CH:16]([NH:14][CH2:13][CH:9]1[C:10]2[C:5](=[CH:4][C:3]([F:2])=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1)([CH3:18])[CH3:15]
Reactant: CC(C)=O
Reactant: NCC1CCCc2cc(F)ccc21
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)NCC1CCCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 75 (1.5 g) was added to a solution of acetone (25 ml) and MeOH (25 ml) then 95% sodium cyanoborohydride (1.32 g) was added in portions. The pH of the reaction was adjusted to ca. pH 5 after complete addition of the NaBH3CN. The reaction was then stirred at room temperature for 8 hrs. The reaction was evaporated to dryness, then dilute HCl and CH2Cl2 (50 ml) was added. The aqueous layer was separated, basified then CH2Cl2 added. The organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was taken up in Et2O (300 ml) then ethereal HCl added. The resulting precipitate was filtered and recrystallized from EtOAc/MeOH giving the desired compound, m.p. 212°-14° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[NH2:19][C:20]1[CH:28]=[C:27]2[C:23]([CH:24]=[N:25][NH:26]2)=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>CCO>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:15][CH3:16])[N:5]=[CH:4][C:3]([C:17]#[N:18])=[C:2]2[NH:19][C:20]1[CH:28]=[C:27]2[C:23]([CH:24]=[N:25][NH:26]2)=[CH:22][CH:21]=1)[CH3:14]
Reactant: CCOc1cc2c(Cl)c(C#N)cnc2cc1OC
Reactant: Nc1ccc2cn[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OC
Yield: 47.1 %

Procedure:
A mixture of 1.00 g (3.82 mmol) of 4-chloro-6-ethoxy-7-methoxyquinoline-3-carbonitrile and 0.609 g (4.58 mmol) of 6-aminoindazole in 20 mL of EtOH was refluxed under N2 for 8 h. Satd NaHCO3 was added, solvent was removed and the residue was azeotroped twice with EtOH. The solid was slurried with cold EtOH, collected, washed twice with H2O and dried. Recrystallization from EtOH yielded 0.646 g of 6-ethoxy-4-(1H-indazol-6-ylamino)-7-methoxyquinoline-3-carbonitrile as tan crystals: mass spectrum (electrospray, m/e): M+H 359.9.
Reaction SMILES: Cl[CH:2]1[C:8]2=[N:9][C:10]3[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:11]=3[CH:12]=[C:7]2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][NH2:27]>>[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][NH:27][CH:2]1[C:8]2=[N:9][C:10]3[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:11]=3[CH:12]=[C:7]2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CCn1ncc2cc3c(nc21)C(Cl)c1ccccc1CC3
Reactant: CN(C)CCCN
Product: CCn1ncc2cc3c(nc21)C(NCCCN(C)C)c1ccccc1CC3
Yield: 76 %

Procedure:
11.8 g. of 11-chloro-1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridine (0.04 mol.), from example 44(a), and 75 ml. of 3-(dimethylamino)propylamine are heated at 120°-125° (bath temperature) for 5.5 hours. Following the procedure of example 44(b), 11 g. (76%) of oily N-[3-(dimethylamino)propyl]-1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]-cyclohepta-[1,2-b]pyrazolo[4,3-e]pyridin-11-amine are obtained. Treatment with ethereal hydrochloric acid yields N-[3-(dimethylamino)propyl]-1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11-amine, hydrochloride (1:2), hydrate (1:2); m.p. 125° (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7](=[S:22])[NH:9][CH3:10]
Reactant: CNC(=O)c1cc(Br)ccc1F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CNC(=S)c1cc(Br)ccc1F
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 99.6 %

Procedure:
A mixture of 5-bromo-2-fluoro-N-methylbenzamide (500 mg, 2 mmol) and Lawesson's reagent (872 mg, 2.16 mmol) in toluene (10 mL) was heated to 100° C. and stirred for 3.5 hours. The reaction was cooled to room temperature, diluted with toluene, and filtered. The filtrate was concentrated and purified by flash column chromatography (0-20% ethyl acetate/heptanes) to give the title compound (494 mg, 92%) as a yellow oil that solidified upon standing. +ESI (M+H+1) 250.1; 1H NMR (400 MHz, CDCl3, δ): 8.20 (dd, J=6.93, 2.63 Hz, 1H), 8.06 (br. s., 1H), 7.47 (ddd, J=8.73, 4.44, 2.63 Hz, 1H), 6.95 (dd, J=11.12, 8.78 Hz, 1H), 3.32 (dd, J=4.88, 0.78 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:8]#[N:9].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH2:8][NH2:9]
Reactant: COCOc1cc(C#N)ccc1-c1ccccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COCOc1cc(CN)ccc1-c1ccccn1
Reaction time: 0.17 h

Procedure:
3-Methoxymethoxy-4-pyridin-2-yl-benzonitrile (160 mg, 0.67 mmol) is then dissolved in ether (10 mL). The resulting solution is slowly added to a suspension of LiAlH4 (100 mg, 2.6 mmol) in Et2O. After addition, the mixture is stirred for another 10 min before quenched with H2O and 5 N NaOH. After which, EtOAc is added and the organic layer is collected and washed with brine and dried over Na2SO4. Removal of the solvent provided the crude amine, which is used directly in the next step. MS (ESI): 245 (M+1)+1.