Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([O:26]C)=O)=[CH:15][C:13]=2[N:14]=1.[F:28][C:29]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:31][C:30]3[CH:32]=[C:33]([F:37])[C:34]([F:36])=[CH:35][C:29]=3[F:28])=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: Nc1cc(F)c(F)cc1F
Reactant: COC(=O)c1cc2nc(Nc3c(C)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3cc(F)c(F)cc3F)c3c(c2[nH]1)CC(C)(C)O3
Yield: 33.8 %

Procedure:
The title compound was prepared by following the procedure described for Example-137 by using methyl 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-35, 0.200 g, 0.414 mmol) and 2,4,5-trifluoroaniline (0.090 g, 0.602 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) and dry toluene (5.0 mL) to afford 0.070 g of the desired product. 1HNMR (DMSO-d6): δ 1.54 (s, 6H), 2.24 (s, 3H), 3.17 (s, 2H), 7.25-7.33 (m, 2H), 7.42 (d, J=8.80 Hz, 1H), 7.52 (s, 1H), 7.72 (q, J=8.4 Hz, 10.8 Hz, 1H), 8.48-8.58 (m, 1H), 9.13 (br s, 1H), 10.16 (s, 1H), 10.98 (br s, 1H): MS [M+H]+: 501.0
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=2)[CH2:11][C:12]2[N:16]3[CH:17]=[C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=4)[CH:19]=[N:20][C:15]3=[N:14][N:13]=2)=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:31]1.C([O-])(=O)C.[K+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:26][N:24]1[CH:25]=[C:21]([C:18]2[CH:19]=[N:20][C:15]3[N:16]([C:12]([CH2:11][C:10]4[CH:9]=[C:8]([C:5]5[N:4]=[CH:3][C:2]([OH:31])=[CH:7][N:6]=5)[CH:29]=[CH:28][CH:27]=4)=[N:13][N:14]=3)[CH:17]=2)[CH:22]=[N:23]1
Reactant: Cn1cc(-c2cnc3nnc(Cc4cccc(-c5ncc(Br)cn5)c4)n3c2)cn1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1cc(-c2cnc3nnc(Cc4cccc(-c5ncc(O)cn5)c4)n3c2)cn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4.03 g of 3-[3-(5-bromopyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazolo[4,3-a]pyrimidine are suspended in 18 ml of THF, heated to 80° C., and 2.86 g of bis(pinacolato)diboron, 2.65 g of potassium acetate and 126 mg of bis(triphenylphosphine)palladium(II)chloride are added and refluxed at 80° C. for 4 h [RM1]. The hot RM is filtered off with suction, rinsed with THF and evaporated to about 30 ml. 30 ml of water and 1.52 g of sodium perborate are then added and stirred at RT overnight. The mixture is acidified using 1 N HCl, THF is distilled off, the precipitate formed is filtered off with suction, washed with water, sucked dry and dried.
Reaction SMILES: [B:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([F:13])[CH:5]=1)([OH:3])[OH:2].CN(C)C(=C(C)C)C.[F:22][C:23]([F:33])([F:32])[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:25].CCOC(C)=O>C(Cl)Cl>[F:13][C:6]1[CH:5]=[C:4]([B:1]([OH:2])[OH:3])[CH:12]=[CH:11][C:7]=1[C:8](=[O:10])[NH:25][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([F:22])([F:32])[F:33]
Reactant: NC(c1ccccc1)C(F)(F)F
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Agent: CC(C)=C(C)N(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NC(c1ccccc1)C(F)(F)F)c1ccc(B(O)O)cc1F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-borono-2-fluorobenzoic acid (54 mg, 0.294 mmol) in DCM (1468 μL) was cooled to 0° C. Then ghosez reagent N,N,3-trimethylbut-2-en-2-amine (65.8 μL, 0.587 mmol) was added and the whole mixture was stirred at rt for 20 min. The mixture was added into a mixture of TEA (246 μL, 1.762 mmol), 2,2,2-trifluoro-1-phenylethanamine (59.1 mg, 0.338 mmol) and DCM (1468 μL). The reaction was stirred at room temperature for 2 h. To the reaction mixture was added EtOAc, and washed with sat. sodium bicarbonate, water, and dried over Na2SO4. Filtered and concentrated to provide the crude product which was taken to the next step without further purification. LCMS (m/z): 342.2 (MH+), 0.84 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10]Cl.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10][O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([CH3:12])(=[O:15])=[O:14])=[CH:21][CH:20]=1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: Cn1c([N+](=O)[O-])cnc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cn1c([N+](=O)[O-])cnc1COc1ccc(S(C)(=O)=O)cc1

Procedure:
17.6 Grams (0.1 mole) of 1-methyl-2-chloromethyl-5-nitro-imidazole were heated for 2 hours at a temperature of from 50° to 60° C, while stirring thoroughly, as has been described in detail in Example 2 above, together with 17.2 g (0.1 mole) of 4-methylsulfonylphenol in 50 ml of dimethylacetamide, in the presence of 13.8 g (0.1 mole) of potassium carbonate. According to the processing method described in Example 1 above, 22.5 g (= 73% of the theory) of 1-methyl-2-(4-methylsulfonyl-phenoxymethyl)-5-nitro-imidazole were obtained in the form of white crystals having a melting point of 157° C.
Reaction SMILES: [C:1]([C:9]1[CH:31]=[CH:30][C:12]([O:13][CH2:14][C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([O:28][CH3:29])[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][OH:33]>C(O)C>[OH:33][N:32]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:31]=[CH:30][C:12]([O:13][CH2:14][C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([O:28][CH3:29])[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1
Reactant: CO[C@@H](Cc1ccc(C#CCOc2ccc(C(=O)c3ccccc3)cc2)cc1)C(=O)O
Reactant: NO
Solvent: CCO
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc(C(=NO)c3ccccc3)cc2)cc1)C(=O)O
Reaction time: 8 h

Procedure:
(2S)-3-{4-[3-(4-Benzoyl-phenoxy)-prop-1-ynyl]-phenyl}-2-methoxy-propionic acid (0.01 mmol, 1 eq) (Example 2) was mixed with Hydroxylamine chlorydrate (4 eq), pyrydine (10 eq) and Ethanol (2 ml) and the mixture reaction was stirred overnight. The ethanol was evaporated under vacuo and HCl 0.5% was added to the residue to pH=3. Extracted with Ethyl Acetate and concentrated to give the title product as a mixture of two oximes. MS(ES) for C26H23NO5 [M+H]+: 430.2, [M−H]−: 428.2.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[C:8]#[N:9].[NH3:12].CO.C([O-])([O-])=O.[Na+].[Na+]>CCOCC>[NH2:12][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: N
Reactant: N#Cc1cc(CBr)ccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: N#Cc1cc(CN)ccc1F

Procedure:
A solution of 5-(bromomethyl)-2-fluorobenzonitrile (300 mg, 1.402 mmol) in 7M NH3/methanol (5 mL, 35.0 mmol) was stirred at room temp for 18 h. After the removing the solvent the resulting residue was stirred with Et2O/sat. Na2CO3. The aqueous layer was then separated and the organic layer dried (Na2SO4), filtered and concentrated to give a 3:1 mixture of the title compound, amine 5-(aminomethyl)-2-fluorobenzonitrile contaminated and 5,5′-azanediylbis(methylene)bis(2-fluorobenzonitrile). The mixture was used without further purification. 1H NMR (500 MHz, CDCl3) δ: 7.48-7.66 (2 H, m), 7.07-7.21 (1 H, m), 3.89 (2 H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[N:10]=[C:11]([N:14]=[C:15]([NH2:17])[NH2:16])[S:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=1.[CH3:18][S:19][C:20](SC)=[N:21][C:22]#[N:23]>C(O)C>[NH2:16][C:15](=[N:14][C:11]1[S:12][CH:13]=[C:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][C:20](=[N:21][C:22]#[N:23])[S:19][CH3:18])[N:8]=2)[N:10]=1)[NH2:17]
Reactant: CSC(=NC#N)SC
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Solvent: CCO
Product: CSC(=NC#N)NCc1cccc(-c2csc(N=C(N)N)n2)n1

Procedure:
A mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.50 g) and dimethyl N-cyanodithioiminocarbonate [(CH3S)2C=N-CN] (0.29 g) in ethanol (10 ml) was refluxed for one hour to give 2-(diaminomethyleneamino)-4-[6-(3-cyano-2-methylisothioureido)methylpyridin-2-yl]thiazole of a crude product. After being concentrated to dry the above product, 40 weight % methanolic methylamine (1.6 ml) and N,N-dimethylformamide (10 ml) was added and the mixture was stirred at 60° C. for 5 hours. The solvent was evaporated in vacuo and the residue was mixed with water. The resulting precipitate was collected by filtration and recrystallized from aqueous N,N-dimethylformamide to give 4-[6-(2-cyano-3-methylguanidino)methylpyridin-2-yl]-2-(diaminomethyleneamino)thiazole (0.42 g).
Reaction SMILES: C(O)(C(F)(F)F)=O.[O:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([C:18](=[O:36])[CH2:19][CH2:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29]COCCOC)=[CH:25][CH:24]=3)=[O:22])[CH:16]=[CH:17][C:9]1=2>C(Cl)Cl>[O:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([C:18](=[O:36])[CH2:19][CH2:20][C:21]([C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)=[O:22])[CH:16]=[CH:17][C:9]1=2
Reactant: COCCOCOc1ccc(C(=O)CCC(=O)c2ccc3c(c2)OCCO3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCC(=O)c1ccc2c(c1)OCCO2)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Neat TFA (0.5 mL) was added to a solution of 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(4-((2-methoxyethoxyl)methoxy)phenyl)butane-1,4-dione 11 (0.35 mmol) in CH2Cl2 (5 mL) stirred at room temperature. The solution was further stirred overnight at room temperature. The volatiles were evaporated under vacuum. The residue was purified by flash chromatography over silica gel eluting with 1% methanol in CH2Cl2 to get 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(4-hydroxyphenyl)butane-1,4-dione 4 as an off white solid (21% yield). 1H NMR (CDCl3, 400 MHz): δ ppm 3.37 (m, 4H), 4.29 (m, 2H), 4.33 (m, 2H), 5.76 (s, 1H), 6.87 (d, J=8.8 Hz, 2H), 6.93 (m, 1H), 7.60 (m, 2H), 7.94 (d, J=8.8 Hz, 2H); ESIMS found C18H16O5 m/z 313 (M+H).
Reaction SMILES: C(=O)([O-])O.[K+].[C:6]1([S:12]([NH:15][C:16]2[CH:17]=[C:18]([C@@H:22]([OH:42])[CH2:23][NH:24][C:25]([CH3:41])([CH3:40])[CH2:26][CH2:27][N:28]3[C:36]4[C:31](=[CH:32][C:33]([C:37]([OH:39])=[O:38])=[CH:34][CH:35]=4)[CH:30]=[CH:29]3)[CH:19]=[CH:20][CH:21]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[CH2:44][C:45]([N:47]([CH3:49])[CH3:48])=[O:46]>CN(C=O)C.O>[C:6]1([S:12]([NH:15][C:16]2[CH:17]=[C:18]([C@@H:22]([OH:42])[CH2:23][NH:24][C:25]([CH3:40])([CH3:41])[CH2:26][CH2:27][N:28]3[C:36]4[C:31](=[CH:32][C:33]([C:37]([O:39][CH2:44][C:45](=[O:46])[N:47]([CH3:49])[CH3:48])=[O:38])=[CH:34][CH:35]=4)[CH:30]=[CH:29]3)[CH:19]=[CH:20][CH:21]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(CCn1ccc2cc(C(=O)O)ccc21)NC[C@H](O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)COC(=O)c1ccc2c(ccn2CCC(C)(C)NC[C@H](O)c2cccc(NS(=O)(=O)c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Potassium hydrogen carbonate (141 mg, 1.4 mmol) is added to a solution of 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3-methyl-butyl}-1H-indole-5-carboxylic acid-hydrotrifluoroacetate (Example 6; 300 mg, 0.47 mmol) in 2 ml DMF. Then the reaction mixture is stirred for 20 minutes at RT and 2-chloro-N,N-dimethylacetamide (143 mg, 1.18 mmol) is added. After 90 hours stirring at RT the reaction mixture is diluted with 50 ml of water and extracted with ethyl acetate. The organic phase is dried on magnesium sulphate and the solvent is eliminated in vacuo. The residue is chromatographed on silica gel (DCM/methanol=100:0→95:5).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:22][CH2:23][N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C(C)C>[OH:8][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][N:24]2[C:25](=[O:34])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]2=[O:33])[CH2:11][CH2:10]1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C1c2ccccc2C(=O)N1CCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 15 g (0.056 mol) of α,α-diphenyl-4-piperidinemethanol, 14.5 g (0.056 mol) of 2-(2-bromoethyl)-1H-isoindole-1,3-dione and 6.7 g (0.063 mol) of sodium carbonate in 150 ml of methyl isobutyl ketone is heated at reflux temperature for 5 hours.
Reaction SMILES: C(#N)C.C([O-])([O-])=O.[Na+].[Na+].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[S:17][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:19][N:20]=2)[CH:11]=1.Cl[C:31]1[CH:40]=[CH:39][C:38]2[CH2:37][CH2:36][CH2:35][C:34](=[O:41])[C:33]=2[N:32]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[S:17][C:18]([C:31]3[CH:40]=[CH:39][C:38]4[CH2:37][CH2:36][CH2:35][C:34](=[O:41])[C:33]=4[N:32]=3)=[CH:19][N:20]=2)[CH:11]=1
Reactant: CC1(C)OB(c2cnc(-c3cccnc3)s2)OC1(C)C
Reactant: O=C1CCCc2ccc(Cl)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1CCCc2ccc(-c3cnc(-c4cccnc4)s3)nc21
Temperature: 80 °C
Yield: 20.9 %

Procedure:
A screw cap vial was charged with acetonitrile (8 mL), water (2.5 mL) and Na2CO3 (1.41 g, 13.0 mmol, 4.7 equiv.) and degassed by bubbling nitrogen through for 10 min. Then 2-(3-pyridyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (800 mg, 2.78 mmol, 1.0 equiv.), 2-chloro-6,7-dihydro-5H-quinolin-8-one (807 mg, 4.44 mmol, 1.6 equiv.) and Pd(PPh3)4 (161 mg, 0.139 mmol, 0.05 equiv.) were added and the mixture was heated to 80° C. for 18 hours. Water was added to the mixture, the aqueous phase was extracted twice with ethyl acetate, the combined organic phase were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluant gradient: Heptane/ethyl acetate 1:0 to 0:1) to afford the title compound (180 mg, 0.58 mmol, 21%) as brown crystals. LCMS (+ve); 0.76 min, 308 (M+1)
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:14]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][NH:25]C(C2C3C(=CC=CC=3)NC=2)=O)[CH2:20][CH2:19]1)[CH2:15][CH2:16][CH3:17]>>[CH2:14]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][NH:25][C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[Cl:1])=[O:13])[CH2:20][CH2:19]1)[CH2:15][CH2:16][CH3:17]
Reactant: O=C(O)c1c(Cl)[nH]c2ccccc12
Reactant: CCCCN1CCC(CNC(=O)c2c[nH]c3ccccc23)CC1
Product: CCCCN1CCC(CNC(=O)c2c(Cl)[nH]c3ccccc23)CC1

Procedure:
2-Chloroindole-3-carboxylic acid (L. Marchetti and A Andreani, Ann. Chim. (Rome), 1973, 63, 681) was converted to its acid chloride and reacted with N-(1-n butyl-4-piperidyl)methylamine (D1) using the procedure of Description 1b to afford N-[(1-n butyl-4-piperidyl)methyl]2-chloroindole-3-carboxamide.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:16][C@H:15]3[C:17]4[CH:18]=[C:19]([C:25]#[N:26])[CH:20]=[CH:21][C:22]=4[O:23][CH2:24][C@@H:14]3[CH2:13]2)[CH2:6][CH2:5]1.[CH3:27][CH2:28][O:29][C:30]1[C:34](=O)[C:32](=[O:33])[C:31]=1[O:36]CC.O>C(O)C>[CH2:28]([O:29][C:30]1[C:31](=[O:36])[C:32](=[O:33])[C:34]=1[NH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:16][C@H:15]3[C:17]4[CH:18]=[C:19]([C:25]#[N:26])[CH:20]=[CH:21][C:22]=4[O:23][CH2:24][C@@H:14]3[CH2:13]2)[CH2:6][CH2:5]1)[CH3:27]
Reactant: N#Cc1ccc2c(c1)[C@@H]1CN(CC[C@H]3CC[C@H](N)CC3)C[C@H]1CO2
Reactant: CCOc1c(OCC)c(=O)c1=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOc1c(N[C@H]2CC[C@H](CCN3C[C@H]4COc5ccc(C#N)cc5[C@@H]4C3)CC2)c(=O)c1=O

Procedure:
2 g of the compound of Example 1 (6.15 mmol) and 0.9 ml of diethyl squarate are stirred at ambient temperature for 2 hours in 15 ml of ethanol. After adding water, the crystals obtained are filtered off and dried in a desiccator to yield the title product in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]3[CH2:14][C@H:15]([OH:17])[CH2:16][C@H:10]3[CH2:9]2)=[CH:6][C:5]([C:18]#[N:19])=[CH:4][C:3]=1[NH:20]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O.ClC(Cl)C>ClCCl>[NH2:20][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([N:8]2[CH2:13][CH2:12][N:11]3[CH2:14][C@H:15]([OH:17])[CH2:16][C@H:10]3[CH2:9]2)[C:2]=1[Cl:1])[C:18]#[N:19]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN3C[C@H](O)C[C@H]3C2)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: N#Cc1cc(N)c(Cl)c(N2CCN3C[C@H](O)C[C@H]3C2)c1
Yield: 79.9 %

Procedure:
(+/−)-tert-butyl (2-chloro-5-cyano-3-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)carbamate (Isomer B, 304 mg, 0.774 mmol) was treated with 25% TFA in dichloroethane (6 ml, 19.47 mmol) at room temperature for 1 h. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate/1N sodium hydroxide (pH 10). The aqueous layer was extracted with dichloromethane two more times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g gold column, eluting with 2-5% 2 N ammonia in methanol/dichloromethane), (+/−)-3-amino-4-chloro-5-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzonitrile (181 mg) was obtained as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)[NH2:7])(=[O:3])[CH3:2].[C:14]([NH:16][C:17]([NH2:19])=[NH:18])#[N:15].[ClH:20]>O>[ClH:20].[C:1]([C:4]1[CH:5]=[C:6]([NH:7][C:14]([NH:16][C:17]([NH2:19])=[NH:18])=[NH:15])[CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: N#CNC(=N)N
Reactant: CC(=O)c1cc(N)cc(C(C)=O)c1
Agent: Cl
Solvent: O
Product: CC(=O)c1cc(NC(=N)NC(=N)N)cc(C(C)=O)c1

Procedure:
Compound No. 12. A suspension of 3,5-diacetylaniline (0.531 g) in water (8 mL) was treated with cyanoguanidine (0.285 g) and conc. HCl (0.25 mL) and heated at reflux. After 6 hr the mixture was cooled and concentrated and 0.248 g of off-white solid was filtered out and dried to give N-(3,5-diacetylphenyl)biguanide hydrochloride, mp 260-70° C. (dec).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[N:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[C@H:28]([NH2:34])[CH2:27]2>CS(C)=O.CO>[N:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[C@H:28]([NH:34][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=1)(=[O:10])=[O:9])[CH2:27]2
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Reactant: N[C@@H]1CN2CCC1CC2
Solvent: CS(C)=O
Solvent: CO
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2N[C@@H]2CN3CCC2CC3)ccc2c1OCC1CC21
Temperature: 140 °C
Yield: 13.8 %

Procedure:
A solution of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67, 0.6 g) and (S)-1-azabicyclo[2.2.2]oct-3-ylamine (6.0 g) in DMSO (6 mL) was stirred and heated in a sealed vessel at 140° C. for 22 hours. After cooling, the mixture was diluted with methanol and concentrated under vacuum. The residue was purified by HPLC (C18) to give (1aRS,7bSR)-5-{2-[((S)-1-azabicyclo[2.2.2]oct-3-yl)amino]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.107 g) as a white solid.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][C:7]([CH3:18])([CH3:17])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:9].N1(C=O)CC[O:22][CH2:21]C1.O>C(OCC)C.O1CCCC1>[CH:21]([C:16]1[C:11]([NH:10][C:8](=[O:9])[C:7]([CH3:18])([CH3:17])[CH3:6])=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:22]
Reactant: O=CN1CCOCC1
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)C(=O)Nc1ncccc1C=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a mixture solution of tert-butyl lithium (1.5M pentane solution, 10 mL, 15 mmol) and diethyl ether (50 mL) was added a solution of 2,2-dimethyl-N-pyridin-2-yl-propionamide described in Preparation Example J-1 (900 mg, 5.0 mmol) in diethyl ether (10 mL) dropwise at −78° C., and the solution was stirred for 90 minutes at the same temperature. At the same temperature, morpholine-4-carbaldehyde (1.0 mL, 10 mmol) was added dropwise, and the solution was warmed gradually to room temperature. Water and tetrahydrofuran were added to the reaction mixture for extraction, the organic layer was washed with brine, then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:4), and the title compound (880 mg, 4.3 mmol, 85%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2.FC(F)(F)C(O)=O.C(Cl)Cl>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn[nH]c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(OCC1(c2ccccc2)CCNCC1)c1cc(Cl)cc2cn[nH]c12

Procedure:
(±)-tert-Butyl 4-((1-(5-chloro-1H-indazol-7-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate (80 mg, 0.17 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was evaporated to afford 50 mg (79%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.37-7.40 (m, 2H), 7.30-7.32 (m, 3H), 7.69 (m, 1H), 4.49 (q, J=6.7 Hz, 1H), 3.40 (d, J=9.2 Hz, 1H), 3.29 (d, J=9.2 Hz, 1H), 2.87-2.93 (m, 2H), 2.67-2.77 (m, 2H), 2.07-2.26 (m, 2H), 1.78-1.93 (m, 2H), 1.41 (m, 3H); 13C-NMR (126 MHz, CDCl3) δ ppm 143.7, 135.7, 133.6, 128.8, 127.9, 127.1, 126.7, 126.0, 124.8, 124.1, 118.9, 78.0, 50.4, 42.6, 41.9, 33.5, 22.1. Mass spec.: 370.17 (MH)+.
Reaction SMILES: Cl[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)=[O:4].Cl.[CH3:17][NH:18][CH3:19].C([O-])([O-])=O.[K+].[K+].O>CC#N>[CH3:17][N:18]([CH3:19])[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)=[O:4]
Reactant: CNC
Reactant: CC(=O)Nc1ccc(C(=O)C(C)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1ccc(C(=O)C(C)N(C)C)cc1
Yield: 89.3 %

Procedure:
A mixture of N-[4-(2-chloro-1-oxopropyl)phenyl]acetamide (0.19 mol), N-methylmethanamine hydrochloride (1:1)(0.38 mol) and K2CO3 (78.8 g) in CH3CN (1400 ml) was stirred and refluxed for 12 hours. The mixture was cooled, poured into water and extracted with CH2Cl2. The organic layer was dried, filtered and the solvent was evaporated, yielding 39.77 g (89%) of (±)-N-[4-[2-(dimethylamino)-1-oxopropyl]phenyl]-acetamide (interm. 9).