Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH2:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:12]1([CH:18]([C:24](OCC)=[O:25])[C:19](OCC)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CCCC)CCCC)CCC.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]1[C:19]([OH:20])=[C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:24]([OH:25])=[N:11][C:6]=21
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: Nc1n[nH]c2cc(Br)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: Oc1nc2c3ccc(Br)cc3nn2c(O)c1-c1ccccc1
Yield: 97.4 %

Procedure:
9.9 g (46.7 mmol) 6-Bromo-1H-indazol-3-ylamine, 11 g (46.7 mmol) diethyl phenylmalonate and 19.8 mL (83.1 mmol) tributyl amine were heated for 15 h at 180° C. The reaction mixture was treated with 2M sodium hydroxide and water and extracted three times with tert-butyl methyl ether. The organic phase was discarded and the aqueous phase was acidified with conc. hydrochloric acid. The precipitate was collected by filtration and washed with water to obtain the desired product (16.2 g) which was however contaminated and which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].[Br:13]Br.O>C(O)(=O)C>[NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([Br:13])=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: BrBr
Reactant: NC(=O)Nc1sccc1C(N)=O
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1sc(Br)cc1C(N)=O
Reaction time: 1.5 h

Procedure:
2-[(Aminocarbonyl)amino]-3-thiophenecarboxamide (1.0 g) was dissolved in acetic acid (20 ml) and a solution of bromine (0.35 ml) in acetic acid (5 ml) was added over 5 minutes with rapid stirring. The mixture was stirred for 90 minutes and then added to water (50 ml). The product was filtered off and washed with water and dried under vacuum (0.55 g).
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:15][O:16][C:17]([C:19]1[S:28][C:22]2[N:23]=[C:24](Cl)[N:25]=[CH:26][C:21]=2[C:20]=1[CH3:29])=[O:18]>>[F:14][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[C:12]([NH:13][C:26]2[C:21]3[C:20]([CH3:29])=[C:19]([C:17]([O:16][CH3:15])=[O:18])[S:28][C:22]=3[N:23]=[CH:24][N:25]=2)=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: COC(=O)c1sc2nc(Cl)ncc2c1C
Reactant: Nc1cccnc1OCC1CC1(F)F
Product: COC(=O)c1sc2ncnc(Nc3cccnc3OCC3CC3(F)F)c2c1C

Procedure:
Prepared analogously to example 32.1 using 2-((2,2-Difluorocyclopropyl)methoxy)pyridin-3-amine (200 mg) and chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (194 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].CC[O-].[Na+].[Na].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:19]=1>O.C(O)C>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([CH2:26][CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CCCc1ccc(Cl)cc1)C(=O)OCC
Reaction time: 2.5 h
Yield: 49.8 %

Procedure:
108.5 g of malonic acid diethyl ester are added dropwise, at 50°, to a sodium ethylate solution freshly prepared from 15.6 g of sodium and 750 ml of ethanol. The mixture is kept at the above temperature for 2.5 hours and 220 g of p-toluenesulphonic acid 3-(4-chlorophenyl)-propyl ester are then added dropwise. After the addition, the mixture is stirred at 50° for 6 hours, 800 ml of water are then added and the mixture is extracted 3 times with a total of 1 liter of diethyl ether. The combined organic phases are dried over sodium sulphate, the solvent is evaporated off and the residue is distilled. 105.6 g of 3-(4-chlorophenyl)-propylmalonic acid diethyl ester of b.p. 145°-155° under 0.01 mm Hg (1.33 Pa) are obtained.
Reaction SMILES: [OH:1][CH:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=1)[CH2:3][NH2:4].[NH2:21][C:22]1[C:23](OCC)=[N:24][S:25](=[O:33])(=[O:32])[C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(#N)C>[OH:1][CH:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=1)[CH2:3][NH:4][C:23]1[C:22]([NH2:21])=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[S:25](=[O:32])(=[O:33])[N:24]=1
Reactant: CCOC(=O)C1=C(N)C(OCC)=NS1(=O)=O
Reactant: NCC(O)COCc1cccc(CN2CCCCC2)c1
Solvent: CC#N
Product: CCOC(=O)C1=C(N)C(NCC(O)COCc2cccc(CN3CCCCC3)c2)=NS1(=O)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.7 %

Procedure:
1.39 g (5 mmol) of 2-hydroxy-3-[3-(1-piperidylmethyl)benzyloxy]propylamine are added dropwise to a suspension of 1.24 g (5 mmol) of 4-amino-3-ethoxy-5-ethoxycarbonylisothiazole-1,1-dioxide in 10 ml of acetonitrile and the mixture is stirred for 5 hours at room temperature. The residue obtained after evaporation of the solvent under vacuum is chromatographed with methanol against silica gel. The main fraction yields 2.06 g (86%) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.Cl[S:32]([C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38])(=[O:34])=[O:33]>>[CH:12]([C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:11]([S:32]([C:35]2[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=2[C:37]([O:39][CH3:40])=[O:38])(=[O:34])=[O:33])[CH:10]=1)=[O:13]
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ccccc1S(=O)(=O)n1cc(C=O)cc1-c1ccccc1
Yield: 60 %

Procedure:
Using 5-phenyl-1H-pyrrole-3-carbaldehyde (513 mg), sodium hydride (60% in oil, 216 mg), 15-crown-5 (990 mg) and methyl 2-(chlorosulfonyl)benzoate (1.06 g), a procedure as in Reference Example 219 was performed to give the title compound as a pale-yellow oil (yield 664 mg, 60%).
Reaction SMILES: [C:1]([C:17](OC)=[O:18])([C:4]([C:7]([C:10]([C:13]([F:16])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[NH2:21][CH2:22][CH2:23][OH:24]>CO>[C:1]([C:17]([NH:21][CH2:22][CH2:23][OH:24])=[O:18])([C:4]([C:7]([C:10]([C:13]([F:14])([F:15])[F:16])([F:11])[F:12])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: COC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: NCCO
Solvent: CO
Product: O=C(NCCO)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
1 mole each of C5F11COOCH3 (made by electrofluorination of hexanoyl chloride and subsequent reaction with methanol, 82 percent linear C5F11) and NH2C2H4OH was heated in methanol (about 200 mL) for 18 hours at 55-60° C. and stripped to provide 355.3 g C5F11CONHC2H4OH, 100 g of which was treated cautiously with 25 mL SOCl2 (obtained from Aldrich Chemical Company, Milwaukee, Wis.), heated for 18 hours at 55-60° C., and stripped to provide 102.1 g C5F11CONHC2H4Cl, 37.5 g of which was dissolved in 100 mL methanol and treated with 6.0 g powdered NaOH. After stirring the resulting mixture for 20 hours at 23° C., the mixture was quenched in water, extracted with dichloromethane, and dried over MgSO4. Distillation of the dried mixture yielded 15.0 g pure C5F11-oxazoline as a colorless liquid (boiling point 170° C.).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:15]=[CH:14][C:10]([CH2:11][C:12]#[N:13])=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[C:12]([CH2:11][C:10]1[CH:14]=[CH:15][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][CH:9]=1)#[N:13]
Reactant: CS(=O)(=O)Cl
Reactant: N#CCc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(CC#N)cc1
Reaction time: 1 h

Procedure:
Methanesulphonyl chloride (3.22 ml, 41.6 mmol) was added dropwise to a solution of 4-aminobenzylcyanide (5.00 g, 37.8 mmol) and triethylamine (5.79 ml, 41.6 mmol) in dichloromethane (30 ml). The reaction mixture was stirred for 1 hour and then poured onto water, the organic layer was separated, dried (MgSO4), filtered and the solvent removed under reduced pressure to afford the title compound as a pale orange solid, 6.50 g.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6](=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].[C:18]1([O:24][CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:25][O:24][C:18]1[CH:23]=[CH:22][C:21]([C:6](=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:20][CH:19]=1
Reactant: COc1ccccc1
Reactant: COC(=O)CCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)CCCCCCC(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88 %

Procedure:
Aluminium chloride (2.58 g) was added to a mixture of methyl 8-chloro-8-oxooctanoate (2.00 g) and anisole (5 ml) at 0° C. After stirring at room temperature for 14 hours, the reaction mixture was poured onto ice (50 g), stirred at room temperature for 1 hour and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain methyl 8-(4-methoxyphenyl)-8-oxooctanoate (2.37 g, yield 88%) as crystals. The crystals were recrystallized from ethyl acetate-hexane to obtain colorless crystals. m.p. 57-58° C.
Reaction SMILES: CS(O[CH:6]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C.O>[N:29]([CH:6]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccncc2)CCN(C)C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2ccncc2)CCN(C)C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a solution of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethyl methanesulfonate (900 mg, 2.18 mmol) in DMF (10 mL) was added sodium azide (212.5 mg, 3.2 mmol) and the reaction mixture was stirred at 100° C. for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 5-(2-azido-2-(pyridin-4-yl)ethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (650 mg). The resulting racemate was purified and resolved by chiral preparative HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.8 (d, 2H), 8.0 (d, 2H), 7.31 (d, 1H), 7.3 (s, 1H), 7.04 (d, 1H), 5.45 (m, 1H), 4.7 (d, 1H), 4.59 (t, 1H), 4.4 (m, 2H), 3.9 (d, 1H), 3.6 (m, 1H), 3.4 (m, 1H), 3.2 (m, 1H), 3.1 (s, 3H), 2.4 (s, 3H).
Reaction SMILES: C1COCC1.[O:6]([C:13]1[CH:14]=[C:15]([N:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=2)[CH2:20][CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:35]([Mg]Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[NH4+].[Cl-]>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.CCO>[O:6]([C:13]1[CH:14]=[C:15]([N:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:29]=2)[CH2:20][CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OC(CN(Cc1cccc(Br)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Reactant: Br[Mg]Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: OC(CN(Cc1cccc(Cc2ccccc2)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Yield: 62 %

Procedure:
To a THF (4 mL) solution of 3-[(3-phenoxyphenyl)[[3-bromophenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (0.60 g, 1.3 mmol) from EX-595B was added benzyl-magnesium bromide in THF (2.0 mL, 2.0 M, 4.0 mmol) and Pd(PPh3)4. The resulting yellow solution was refluxed under N2 for 18 h. The cooled solution was poured into saturated aq. NH4Cl, extracted with ethyl acetate, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 15% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.39 g (62%) of the desired 3-[(3-phenoxyphenyl)[[3-(phenylmethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a colorless oil. Anal. calcd. for C29H26NO2F3.0.4 EtOH: C, 72.17; H, 5.77; N, 2.82. Found: C, 72.17; H, 5.42; N, 2.83. HRMS calcd. 478.1994 ([M+H]+, found: 478.1984. 1H NMR (C6D6) δ 1.58 (d, 1H), 3.22 (dd, 1H), 3.46 (dd, 1H), 3.69 (s, 2H), 3.73 (m, 1H), 4.18 (s, 2H), 6.34 (dd, 1H), 6.47 (dd, 1H), 6.53 (t, 1H), 6.8-7.1 (m 15H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:3]=12.[Li].Cl.[CH3:16][O:17][C:18](=[O:23])[C@H:19]([CH2:21][OH:22])[NH2:20].CCN(CC)CC>O=S(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([NH:20][C@H:19]([C:18]([O:17][CH3:16])=[O:23])[CH2:21][OH:22])=[O:13])[S:10][C:3]=12
Reactant: O=C(O)c1cc2nccc(Cl)c2s1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Agent: [Li]
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NC(=O)c1cc2nccc(Cl)c2s1
Yield: 54.2 %

Procedure:
This material was prepared from lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylic acid (2.69 g, 12.25 mmole), SOCl2 (10 ml), L-serine methyl ester hydrochloride (2.86 g, 18.4 mmole) and Et3N (5.12 ml, 37.7 mmole) in a manner as previously described for example 9d to give a white solid (2.09 g, 54%). 1H NMR (300 MHz, CDCl3) δ8.61 (1H, d, J=5.1 Hz), 8.02 (1H, s), 7.35 (1H, d, J=5.1 Hz), 4.89 (1H, m), 4.15 (2H, m), 3.84 (3H, m).
Reaction SMILES: C(N=C=NCCCN(C)C)C.[OH:12]N1C2C=CC=CC=2N=N1.Cl.[CH:23]([N:26]1[C:30]2[C:31](=[O:40])[NH:32][C:33]3([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[CH2:34][C:29]=2[CH:28]=[N:27]1)([CH3:25])[CH3:24].[CH:41]([N:44]1[C:48]2C(=O)N[C:51]3([CH2:57]CN[CH2:54][CH2:53]3)[CH2:52][C:47]=2[CH:46]=[N:45]1)(C)C>CN(C)C=O.O>[CH:23]([N:26]1[C:30]2[C:31](=[O:40])[NH:32][C:33]3([CH2:39][CH2:38][N:37]([C:57]([C:51]4[CH:53]=[CH:54][C:46]5[C:47](=[CH:48][N:44]([CH3:41])[N:45]=5)[CH:52]=4)=[O:12])[CH2:36][CH2:35]3)[CH2:34][C:29]=2[CH:28]=[N:27]1)([CH3:25])[CH3:24]
Reactant: On1nnc2ccccc21
Reactant: CC(C)n1ncc2c1C(=O)NC1(CCNCC1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ncc2c1C(=O)NC1(CCN(C(=O)c3ccc4nn(C)cc4c3)CC1)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-methyl-2H-indazole-5-carboxyllic acid (28 mg, 0.16 mmol) in dry dimethylformamide was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (37 mg, 0.19 mmol) and 1-hydroxybenzotriazole (26 mg, 0.19 mmol) N,N-diisopropylethylamine (84 μL, 0.48 mmol). The reaction mixture was stirred at room temperature for 10 minutes and then 1′-isopropyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(1′H)-one hydrochloride was added (Intermediate 2, 30 mg, 0.12 mmol) and the reaction was stirred for 16 hours. The mixture was poured into chilled water and the resulting precipitate was collected by vacuum filtration. The obtained solid was triturated from diethyl ether to afford 1′-isopropyl-1-(2-methyl-2H-indazole-5-carbonyl)-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(1′H)-one (25 mg). +ESI (M+H) 407.3; 1H NMR (400 MHz, DMSO-d6, δ): 8.41 (s, 1H), 7.85 (s, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 7.40 (s, 1H), 7.20 (s, 1H), 5.40 (m, 1H), 4.18 (s, 3H), 3.60 (br. s., 4H), 2.85 (s, 2H), 1.70 (br. s., 4H), 1.35 (d, 6H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1)CCC>CN(C=O)C.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.[Cu]I>[CH3:12][O:11][C:5]1[CH:4]=[N:3][C:2]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: COc1cnc(Br)c2[nH]ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cnc(-c2cnccn2)c2[nH]ccc12
Temperature: 90 °C
Yield: 52.9 %

Procedure:
A mixture of 7-bromo-4-methoxy-6-azaindole (1.160 g, 5.11 mmol) and 2-(tri-n-butylstannyl)pyrazine (2.07 g, 5.62 mmol) in 25 mL of dry DMF was degassed with a stream of Ar bubbles for 10 min. To this solution was added tetrakis(triphenylphosphine)palladium (0.590 g, 0.511 mmol) and CuI (0.097 g, 0.511 mmol) and the mixture was heated in a sealed tube at 90° C. for 4 h. The cooled mixture was filtered through methanesulfonic acid SCX cartridges (7×3 g) with MeOH, to remove triphenylphosphine oxide. The filtrate was evaporated and the residue triturated with MeOH to give the title compound (0.612 g, 53%) as a light yellow solid:
Reaction SMILES: [H-].[Na+].CCCCCC.[CH2:9]([OH:12])[CH:10]=[CH2:11].[Cl:13][C:14]([Cl:18])([Cl:17])[C:15]#[N:16]>CCOCC>[Cl:13][C:14]([Cl:18])([Cl:17])[C:15](=[NH:16])[O:12][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCO
Reactant: N#CC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: C=CCOC(=N)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of 80% sodium hydride (945 mg., 31.5 mmol.; washed twice with 25 ml. of hexane) in dry ether (30 ml.) was treated dropwise with a solution of 2-propen-1-ol (21.4 ml., 18.3 g., 315 mmol.), in dry ether (45 ml.), stirred for 20 minutes at room temperature under argon and then cooled to 0° C. (ice-salt bath). Trichloroacetonitrile (30 ml. or 42.3 g., 0.30 mole) was added over a period of 15 minutes and the brownish solution was stirred at 0° C. for 40 minutes, at 10° C. for 10 minutes and at room temperature for 10 minutes. The reaction mixture was concentrated to a syrup, treated with a solution of methanol (1.2 ml.) in pentane (30 ml.) and stirred vigorously for 5.0 minutes. The light brown precipitates were filtered off, washed with pentane (2×30 ml.) and the combined filtrates concentrated down to a light brown liquid. The liquid was re-dissolved in pentane (30 ml.), stirred for a few minutes, and the resulting suspension filtered, and the precipitates obtained washed with pentane (30 ml.), repeating the procedure at least one more time. The clear filtrate was concentrated and dried in vacuo to give 54.0 g. of title compound as a light red-colored liquid. This material was stored as a solution in hexane at 10° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH2:8][CH2:7]2.[B-](F)(F)(F)[F:13].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CO>[F:13][CH:8]1[CH2:7][C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)[C:9]1=[O:11]
Reactant: Cc1cccc2c1C(=O)CC2
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CO
Product: Cc1cccc2c1C(=O)C(F)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-methyl-1-indanone (CAS No. 39627-61-7,513 mg, 3.51 mmol) in MeOH (18 mL) was added Selectfluor™ (1.49 g, 4.21 mmol) at room temperature. The reaction mixture was heated for 2 hours under reflux. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was treated with DCM and the insoluble matter was filtered off. The filtrate was concentrated in vacuo. The residue was dissolved in MeCN (10 mL) and 5 N HCl (5 mL). The solution was stirred at room temperature for 30 mins. After concentration of the solution in vacuo, the residue was partitioned between AcOEt and H2O. The aqueous layer was extracted with AcOEt twice. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (555 mg, 3.38 mmol).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:5]=1.[O:16]=[C:17]1[NH:26][C:25]2[N:24]=[C:23]([O:27][CH2:28][CH2:29][CH2:30][CH:31]=O)[CH:22]=[CH:21][C:20]=2[CH:19]=[CH:18]1>>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:11][CH2:12][N:13]([CH2:31][CH2:30][CH2:29][CH2:28][O:27][C:23]3[N:24]=[C:25]4[C:20]([CH:19]=[CH:18][C:17](=[O:16])[NH:26]4)=[CH:21][CH:22]=3)[CH2:14][CH2:15]2)[N:5]=1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Reactant: COc1ccnc(N2CCNCC2)n1
Agent: Cl
Product: COc1ccnc(N2CCN(CCCCOc3ccc4ccc(=O)[nH]c4n3)CC2)n1

Procedure:
In a manner similar to that of other examples above, 4-methoxy-2-piperazin-1-yl-pyrimidine hydrochloride (U.S. Pat. No. 6,303,603) was coupled by reductive amination to 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 411.2 (Exact Mass: 410.21).
Reaction SMILES: [CH2:1]1[C:10]2[C:5]3=[C:6]([CH2:11][CH2:12][C:13](=[O:14])[N:4]3[CH2:3][CH2:2]1)[CH:7]=[CH:8][CH:9]=2.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([C:8]1[CH:9]=[C:10]2[C:5]3=[C:6]([CH2:11][CH2:12][C:13](=[O:14])[N:4]3[CH2:3][CH2:2][CH2:1]2)[CH:7]=1)=[O:22]
Reactant: O=C(Cl)CCCCCBr
Reactant: O=C1CCc2cccc3c2N1CCC3
Product: O=C(CCCCCBr)c1cc2c3c(c1)CCC(=O)N3CCC2

Procedure:
Using 2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one and 6-bromohexanoyl chloride according to the same method as that of Reference Example 1, the title compound (3.90 g) was obtained as colorless crystals having a melting point of 52–53° C.
Reaction SMILES: [N+](=[CH2:3])=[N-].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]=[C:13]([C:15]([N+:18]([O-:20])=[O:19])=[N:16][OH:17])[CH2:12][N+:11]([O-:21])=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:9]=2[CH:29]=1>CCOCC.C(Cl)Cl>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]=[C:13]([C:15]([N+:18]([O-:20])=[O:19])=[N:16][O:17][CH3:3])[CH2:12][N+:11]([O-:21])=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:9]=2[CH:29]=1
Reactant: C=[N+]=[N-]
Reactant: O=[N+]([O-])C(=NO)C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=[N+]([O-])C1
Solvent: ClCCl
Solvent: CCOCC
Product: CON=C(C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=[N+]([O-])C1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of diazomethane in ether was added to a suspension of 3.8 g (0.01 mol) of 7-chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methanimine 4-oxide in 200 ml of methylene chloride. The mixture was stirred for 1 hr at room temperature whereby a clear solution resulted. The excess diazomethane was destroyed by addition of acetic acid. The reaction mixture was washed with aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated. Crystallization of the residue from ether yielded yellow crystals. The analytical sample was recrystallized from ether, mp 207°-209° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1COc1ccc(F)c(F)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2ccc(F)c(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(3,4-difluorophenoxy)methyl]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):