Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].[C:8]([C:11]1[CH:42]=[C:41]2[C:14]([CH2:15][C:16]3[C:20]([C:21](=[O:34])[CH:22]([C:32]#[N:33])[C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:24])=[N:19][N:18]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:17]=32)=[CH:13][CH:12]=1)(O)=[O:9].C1(N=C=NC2CCCCC2)CCCCC1.CN(CCO)C>C(#N)C.C(N(CC)CC)C>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][C:8]([C:11]1[CH:42]=[C:41]2[C:14]([CH2:15][C:16]3[C:20]([C:21](=[O:34])[CH:22]([C:32]#[N:33])[C:23](=[O:24])[NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:19][N:18]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:17]=32)=[CH:13][CH:12]=1)=[O:9]
Reactant: COC(=O)CN
Reactant: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1Cc1ccc(C(=O)O)cc1-2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)CCO
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1ccc2c(c1)-c1c(c(C(=O)C(C#N)C(=O)Nc3ccccc3)nn1-c1ccccc1)C2
Temperature: 25 °C
Yield: 45.2 %

Procedure:
Glycine methyl ester hydrochloride (0.7 g) suspended in anhydrous acetonitrile (250 ml) is treated with triethylamine (0.56 g) under stirring at room temperature. To the suspension first 3-(7-carboxy-1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazole-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide (2.3 g) and the dicyclohexylcarbodiimide (1.25 g) are added. The reaction mixture is kept under stirring at room temperature for 4 hours and then is basified to pH 8 by adding dimethylaminoethanol. The precipitate is filtered, washed with acetonitrile and then eliminated. The organic solution is concentrated in vacuo to a small volume, diluted with water, acidified to pH 2 with 1N HCl and then basified to pH 8 with 1N NaOH. The obtained precipitate is filtered, washed with water, dissolved in chloroform and washed with 1N HCl and then with water until neutral. The organic solution is evaporated in vacuo to dryness and the residue is purified over a SiO2 column using CHCl3 /methanol 90/10 as eluent. Final crystallization from CH2Cl 2 /ethyl acetate yields 1.2 g of pure N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyano-acetyl)indeno[1,2-c]pyrazol-7-yl] carbonyl-glycine methyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH2:10][CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([CH3:26])[CH:20]=[C:19]2[NH2:27])=[O:14].C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:10][CH2:11][CH2:12][C:13]([NH:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21]([CH3:26])[CH:20]=[C:19]3[NH2:27])=[O:14])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(N)c2cc(NC(=O)CCN)ccc2n1
Reactant: Cc1cc(Cl)nc(N)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NCCC(=O)Nc2ccc3nc(C)cc(N)c3c2)nc(N)n1
Yield: 36.6 %

Procedure:
A solution of 0.05 g (0.35 mmol) 2-amino-4-chloro-6-methylpyrimidine, 0.204 mg (0.35 mmol) 3-amino-N-(4-amino-2-methyl-quinolin-6-yl)-propionamide and 0.18 mg (1.39 mmol) diisopropyl ethylamine in 5 ml dimethylacetamide was stirred at 100° C. for 2 h. After evaporation of the solvent the residue was purified by HPLC and lyophilized to yield 45 mg of the title compound. MS 352.3 (M+H)+, 1H-NMR (DMSO-d6)δ 2.20 (s, 3H), 2.55 (s, 3H), 2.70 (m, 2H), 3.65 (m, 2H), 6.1 (s, NH), 7.70–7.90 (m, 5H), 8.60–8.80 (br.s., NH), 13.85 (br.s., NH).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[N+:14]([O-])([OH:16])=[O:15].[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1ccc(-c2ccccc2)nn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccccc1-c1ccc(Cl)nn1
Temperature: 0 °C

Procedure:
To an ice-cold solution of 3-chloro-6-phenylpyridazine (Aldrich, 1.4 g, 7.5 mmol) in conc. sulfuric acid (30 mL) was added 90% nitric acid (0.6 mL, 15 mmol). After 15 min. the mixture was poured over ice (200 mL) and neutralized with 25% aq. NaOH. The resulting precipitate was collected by filtration and dried under vacuum. The crude product (1.84 g) was a 1:1:0.5 mixture of ortho:meta para isomers.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C@@H:12]([OH:23])[CH2:11][C@H:10]1[OH:24].[C:26]1([C:37]2CCCCCCCCCC=2)[CH2:36]CCCCCCCNN=1.C(I)CC>CC(C)=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH:26]([CH3:37])[CH3:36])=[O:21])[C@@H:12]([OH:23])[CH2:11][C@H:10]1[OH:24]
Reactant: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Solvent: CCCI
Solvent: CC(C)=O
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC(C)C)[C@@H](O)C[C@H]1O
Reaction time: 8 h

Procedure:
20 mg (0,056 mmol) of 11 epi PGF2alpha (Cayman Chemicals, U.S.) were dissolved in acetone at room temperature. To this solution were added 54.5 mg (0.336 mmol) of diazabicycloundecene (DBu) and 76.15 mg (0.448 mmol) of propyl iodide, whereupon the mixture was left to stand at room temperature for 8 hours. The solvent was removed in vacuo, the residue then being dissolved in 50 ml of ethyl acetate, washed with 20 ml of water, 20 ml of 3% citric acid and 5% sodium hydrogen carbonate; thereafter the organic phase was dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by means of column chromatography on silica gel, with ethyl acetate-acetone (1:1) as the eluent. The yield of the product was about 76%, and its purity was tested by means of thin layer chromatography and NMR.
Reaction SMILES: [F:1][C:2]([F:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.O.[OH-].[Li+].[C:22]([O:25][C@@H:26]1[C@H:30]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C@@H:29]([CH:41]=O)[C@H:28]([O:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[CH2:27]1)(=[O:24])[CH3:23]>COC(C)(C)C.O>[C:22]([O:25][C@@H:26]1[C@H:30]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C@@H:29](/[CH:41]=[CH:4]/[C:3](=[O:11])[C:2]([F:1])([F:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:28]([O:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[CH2:27]1)(=[O:24])[CH3:23]
Reactant: COP(=O)(CC(=O)C(F)(F)c1ccccc1)OC
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: COC(=O)CCCCCC[C@@H]1[C@@H](/C=C/C(=O)C(F)(F)c2ccccc2)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxo-3-phenylpropyl)phosphonate (6) (0.262 g, 0.942 mmol) in t-butyl methyl ether (7 ml), lithium hydroxide monohydrate (38.2 mg, 0.910 mmol) was added and the mixture was stirred for one hour at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyl-oxy)cyclopentyl]heptanate (2) (0.250 g, 0.627 mmol) in t-butyl methyl ether (3 ml) and water (0.3 ml) were added thereto, and the mixed solution was heat refluxed for approximately 48 hours. After cooling to room temperature, the reaction mixture was added to water, and extracted twice with t-butyl methyl ether. The organic layers were combined, sequentially washed with water, saturated sodium bicarbonate water and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Merck Art. 9385: 200 g; ethyl acetate:hexane=2:3). The fractions containing impurities were re-purified by silica gel column chromatography (Merck Art. 9385: 120 g; ethyl acetate:hexane=2:3), to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-4-phenyl-1-butenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (7) (0.257 g; 0.467 mmol; yield: 74.4%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].[C:9](Cl)(=O)C1C=CC=CC=1.C(=O)(OC)OC>>[O:4]([CH3:9])[S:3]([C:2]([F:8])([F:7])[F:1])(=[O:6])=[O:5]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: O=C(Cl)c1ccccc1
Solvent: COC(=O)OC
Product: COS(=O)(=O)C(F)(F)F
Temperature: 90 °C
Yield: 96.6 %

Procedure:
A further 49.15 g (0.328 mol) of trifluoromethanesulfonic acid, 46.10 g (0.328 mol) of benzoyl chloride and 29.49 g (0.328 mol) of dimethyl carbonate are added to the distillation residue with stirring. The reaction mixture is subsequently heated at 90° C. using an oil bath (temperature in the oil bath) for 6 hours, giving 52.00 g (yield: 96.8%) of pure methyl triflate by distillation.
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1>[Fe]>[NH2:9][C:5]1[CH:6]=[C:7]([I:8])[C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(I)c1
Agent: [Fe]
Product: Nc1cnc(Cl)c(I)c1
Yield: 76.8 %

Procedure:
2-Chloro-3-iodo-5-nitropyridine (0.25 g, 0.88 mmol) was reacted with iron powder (0.25 g, 4.4 mmol) in the manner described in example 762D. Removal of the solvent in vacuo gave compound 765C (0.172 g, 77%). as a golden yellow solid. HPLC: 100% at 2.32 min(YMC S5 ODS column) eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS (ES): m/z 255.03 [M+H]+.
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[CH3:4][C:5]1[C:9]([Zr+3:11])([CH3:10])[C:8]([CH3:12])=[C:7]([CH3:13])[C:6]=1[CH3:14].[CH3:15][C:16]1[C:17]([CH3:24])=[C:18]([CH3:23])[C:19]([Li])([CH3:21])[CH:20]=1>O1CCCC1>[Cl-:1].[Cl-:1].[CH3:4][C:5]1[C:9]([Zr+2:11][C:19]2([CH3:21])[CH:20]=[C:16]([CH3:15])[C:17]([CH3:24])=[C:18]2[CH3:23])([CH3:10])[C:8]([CH3:12])=[C:7]([CH3:13])[C:6]=1[CH3:14]
Reactant: CC1=C(C)C(C)([Zr+3])C(C)=C1C
Reactant: [Li]C1(C)C=C(C)C(C)=C1C
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC1=CC(C)([Zr+2]C2(C)C(C)=C(C)C(C)=C2C)C(C)=C1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
10.0 g (33.6 mmols) of (pentamethylcyclopentadienyl)zirconium trichloride, and 150 ml of tetrahydrofuran were put into a 300-ml two-neck egg-plant flask. To this, dropwise added was a tetrahydrofuran solution (50 ml) of 4.3 g (33.6 mmols) of (tetramethylcyclopentadienyl) lithium that had been separately prepared at 0° C. This was warmed up to room temperature, and then stirred as such for 8 hours. The solvent was evaporated away, and the residue was extracted in 100 ml of dichloromethane. The resulting extract was concentrated and cooled to −20° C. to obtain 5.8 g of (pentamethylcyclopentadienyl)(tetramethylcyclopentadienyl)zirconium dichloride. A part of this was collected and dissolved in dewatered toluene to prepare a catalyst solution having a concentration of 10 μmols/ml.
Reaction SMILES: [C:1]1([N:7]2[C:15]([NH2:16])=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)(=O)C.[Na]>C(Cl)Cl>[CH:17]1([NH:16][C:15]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]3[C:14]=2[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCCCC1
Reactant: Nc1c2ccccc2nn1-c1ccccc1
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Yield: 18 %

Procedure:
To a solution of 2-phenyl-2H-indazol-3-amine (800 mg, 4 mmol; Shirtcliff, Laura D.; Rivers, Jazmin; Haley, Michael M, Journal of Organic Chemistry (2006), 71(17), 6619-6622) in CH2Cl2 (43 ml) was added cyclohexanone (1.97 ml, 19 mmol; CAS Reg. No. 108-94-1), acetic acid (0.22 ml, 4 mmol) and sodium triacetoxyborhydride (2.43 g, 11 mmol) at ambient temperature under an argon atmosphere. The reaction mixture was heated under reflux conditions for 12 h, poured onto ice water/aqueous NaHCO3 solution 1/1 and extracted two times with CH2Cl2. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure, the resulting brown oil was dissolved in MeOH (20 ml) and heated under reflux conditions for 30 min. Removal of the solvent under reduced pressure left a brown oil which was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (206 mg, 0.7 mmol; 18%) as yellow oil. MS: m/e=292.4 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([CH3:21])[C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:20])=[O:9])=[CH:4][CH:3]=1.C([O:26][CH:27]=[C:28]([C:34](OCC)=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30])C>>[CH2:32]([O:31][C:29]([CH:28]1[C:27](=[O:26])[C:15]2[C:14](=[C:13]3[C:18](=[CH:17][CH:16]=2)[CH:19]=[C:10]([C:8](=[O:9])[N:7]([CH2:6][C:5]2[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:21])[CH:11]=[N:12]3)[N:20]=[CH:34]1)=[O:30])[CH3:33]
Reactant: CN(Cc1ccc(F)cc1)C(=O)c1cnc2c(N)cccc2c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C1C=Nc2c(ccc3cc(C(=O)N(C)Cc4ccc(F)cc4)cnc23)C1=O
Yield: 64 %

Procedure:
Using a procedure analogous to that described in Example 2, in the section relating to the preparation of starting materials, 3-[N-(4-fluorobenzyl)-N-methylcarbamoyl]-8-aminoquinoline was reacted with diethyl ethoxymethylenemalonate to give 3-ethoxycarbonyl-8-[N-(4-fluorobenzyl)-N-methylcarbamoyl]-4-oxo-3,4-dihydro-1,10-phenanthroline in 64% yield, mp 206-207° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[C:13](=[C:14]=[O:15])[N:12]([CH3:16])[C:11]2[N:10]=[C:9]3[CH:17]=[C:18](F)[C:19]([F:21])=[CH:20][C:8]3=[CH:7][C:6]=2[C:5]1=[O:23])[CH3:2].Cl.Cl.[CH2:26]([N:28]([CH2:33][CH3:34])[CH:29]1[CH2:32][NH:31][CH2:30]1)[CH3:27]>>[CH2:26]([N:28]([CH2:33][CH3:34])[CH:29]1[CH2:32][N:31]([C:18]2[C:19]([F:21])=[CH:20][C:8]3[C:9]([CH:17]=2)=[N:10][C:11]2[N:12]([CH3:16])[C:13](=[C:14]=[O:15])[CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:23])[C:6]=2[CH:7]=3)[CH2:30]1)[CH3:27]
Reactant: CCN(CC)C1CNC1
Reactant: CCOC1C(=O)c2cc3cc(F)c(F)cc3nc2N(C)C1=C=O
Agent: Cl
Product: CCOC1C(=O)c2cc3cc(F)c(N4CC(N(CC)CC)C4)cc3nc2N(C)C1=C=O

Procedure:
8-(3-Diethylamino-1-azetidinyl)-3-ethoxy-carbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 2, but starting with 2 g of 3-ethoxy-carbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine and 1.4 g of 3-(diethylamino)-azetidine dihydrochloride. After recrystallization of the crude product in 500 cm3 of methanol, 2.07 g of 8-(3-diethylamino-1-azetidinyl)-3-ethoxy-carbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine are obtained in the form of a yellow solid, melting point 260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-])=O)[CH2:13][C:12]([CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20]2)=[CH:11][CH2:10]1>CO.C(O)(=O)C.[Zn]>[NH2:15][C@@H:14]1[CH2:13][C:12]([CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20]2)=[CH:11][CH2:10][C@H:9]1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: CCOC(=O)[C@@H]1CCCN(CC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H]([N+](=O)[O-])C2)C1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1CCCN(CC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H](N)C2)C1
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of Example 18A (100 mg, 0.24 mmol) in a mixture of methanol/acetic acid (1.0 mL/1.0 mL), Zn powder (170 mg, 2.6 mmol) was added at room temperature. The reaction mixture was stirred for 30 minutes, filtered, concentrated under reduced pressure and purified by high pressure liquid chromatography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (78 mg, 78%). 1H NMR (400 MHz, methanol-d4) δ ppm 7.62 (br s, 1H), 7.51 (br s, 1H), 7.39 (br s, 1H), 6.30-6.20 (m, 1H), 4.21 (q, 2H), 3.95-3.85 (m, 1H), 3.8-3.5 (m, 4H), 3.15-2.80 (m, 4H), 2.75-2.40 (m, 3H), 2.35-2.20 (m, 2H), 2.10-1.90 (m, 2H), 1.65-1.50 (m, 1H), 1.30 (t, 3H). MS (DCI) m/z 411 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[N:10][N:9]=1.N1C=NN=N1.[C:18](=[O:21])([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:8]([O:21][CH2:18][N:9]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])=[N:12][N:11]=[N:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: Brc1ccccc1-c1nnn[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: c1nnn[nH]1
Solvent: CN(C)C=O
Product: Brc1ccccc1-c1nnnn1COCc1ccccc1
Yield: 70 %

Procedure:
5-(2-Bromophenyl)-[1H]-tetrazole was nitrogen-protected as the benzyloxymethyl (BOM) ether by reaction of a solution of the tetrazole in anhydrous dimethylformamide with technical grade BOM-chloride and anhydrous potassium carbonate. The reaction was complete in less than 60 minutes and the work up involved filtration through Celite and evaporation of the solvent under reduced pressure. The residue obtained was purified by chromatography to afford the title product in 70% yield as an oil which crystallized on standing.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH2:12])=O)(=[O:3])[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>N1C=CC=CC=1>[C:1]([O:4][CH:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:6][CH2:7][CH2:8][NH:9][C:10]#[N:12])(=[O:3])[CH3:2]
Reactant: CCCCCC(CCCNC(N)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCC(CCCNC#N)OC(C)=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 4-acetoxynonylurea (2.4 g., 0.01 mole) in pyridine (10 ml.) is added p-toluene-sulfonyl chloride (2.0 g., excess) in one portion. The reaction is stirred at room temperature for six hours then poured into water (150 ml.). The aqueous mixture is extracted with ether (3 × 75 ml.), the ether is washed with 5% hydrochloric acid, brine, and dried over sodium sulfate. The solvent is removed in vacuo to give 4-acetoxynonylcyanamide as a residual oil.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.[Sn](CCCC)(CCCC)(Cl)Cl.C1([SiH3])C=CC=CC=1>C1COCC1>[N:15]1([C:18]2[CH:19]=[CH:20][C:21]([NH:22][CH2:1][C:3]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=3)=[CH:23][CH:24]=2)[CH2:14][CH2:13][O:12][CH2:17][CH2:16]1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CNc2ccc(N3CCOCC3)cc2)cc1

Procedure:
A suspension of 4-formylbenzoic acid (2.53 g; 16.8 mmol; 1 eq), 4-morpholinoaniline (3 g; 16.8 mmol; 1 eq) and Bu2SnCl2 (510 mg; 1.68 mmol; 0.1 eq) in dry THF (20 ml) was treated with PhSiH3 (3.31 ml; 16.8 mmol; 1 eq) at room temperature for 12 h. The reaction was filtered and the solid product was washed with MeOH. The yield of the reaction was 5.25 g (99%). LRMS: calc 312.37; found: 313.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([C@H:18]1[C:25]2[CH:24]=[N:23][N:22]([CH3:26])[C:21]=2[CH2:20][NH:19]1)=[O:17].[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=2)[CH:29]=[CH:28]1.CCN(C(C)C)C(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([C@H:18]1[C:25]2[CH:24]=[N:23][N:22]([CH3:26])[C:21]=2[CH2:20][N:19]1[C:36]([C:33]1[CH:34]=[C:35]2[C:30]([CH:29]=[CH:28][NH:27]2)=[CH:31][CH:32]=1)=[O:37])=[O:17]
Reactant: Cn1ncc2c1CN[C@H]2C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc2c1CN(C(=O)c1ccc3cc[nH]c3c1)[C@H]2C(=O)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
A solution of (R)-1-methyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazole-4-carboxylic acid [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide (example 1B), 38 mg), 6-indolecarboxylic acid (22 mg), 0.03 ml (DIPEA) and BOPCl (51 mg) in 2 ml acetonitrile was stirred for 2 hrs at 0° C. A consecutive basic and acidic work up delivered a yellow oil which was purified by chromatography (silica gel, AcOEt). (R)-5-(1H-Indole-6-carbonyl)-1-methyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazole-4-carboxylic acid [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide was obtained as a white solid (13 mg). MS: 497.0 (M+H)+
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([CH:8]1[C:16]2[C:15](O)=[N:14][CH:13]=[N:12][C:11]=2[CH2:10][CH2:9]1)[CH3:7].C(#N)C>>[Cl:3][C:15]1[C:16]2[CH:8]([CH2:6][CH3:7])[CH2:9][CH2:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC1CCc2ncnc(O)c21
Solvent: CC#N
Product: CCC1CCc2ncnc(Cl)c21
Temperature: 80 °C
Reaction time: 15 h
Yield: 26.6 %

Procedure:
Phosphorous oxychloride (1.92 mL, 20.6 mmol) was added to a solution of 5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (1.13 g, 6.88 mmol) in acetonitrile (40 mL, 766 mmol) and heated to 80° C. The reaction was stirred at 80° C. for 15 hours. LCMS confirmed consumption of the starting material peak and conversion to a new product peak. The reaction was cooled to room temperature and concentrated under vacuum. The residue was partitioned between DCM and saturated aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4. The crude solution was concentrated under vacuum to an oil. The crude was purified by silica gel chromatography (gradient: 10-50% EtOAc/Hexanes). Purification provided 4-chloro-5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (334 mg, 1.83 mmol, 26.6% yield) as an oil. MS (APCI+) [M+H]: 183.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[Li+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: COC(=O)c1cc(Br)cc2cc[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Br)cc2cc[nH]c12
Yield: 99.4 %

Procedure:
Methyl 5-bromo-1H-indole-7-carboxylate (5 g, 19.7 mmol) was dissolved in methanol (200 mL) and a solution of lithium hydroxide (0.99 g, 41 mmol) in water (10 mL) was added. The mixture was heated at reflux for 50 hours. The methanol was removed in vacuo and the residue diluted with aqueous hydrochloric acid (2 M). The resulting precipitate was filtered off and dried in a heated vacuum pistol to give 4.7 g (99%) of the title compound as a beige solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].C([O-])([O-])=O.[Na+].[Na+].[C:16](Cl)([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17]>O.O1CCOCC1>[CH:31]1[C:32]2[CH:20]([CH2:19][O:18][C:16]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]3[C:7]([OH:9])=[O:8])=[O:17])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]=2[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)[C@@H]1CCCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1CCCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.8 %

Procedure:
To a stirred mixture of (S)-piperidine-2-carboxylic acid (1.0 g, 7.75 mmol) and Na2CO3 (1.65 g, 15.50 mmol) in water (10 mL) was added a solution of FMOC-Cl (3.0 g, 11.63 mmol) in 1,4-dioxane (10 mL) dropwise at 0° C. and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (50 mL) and washed with MTBE (25 mL). The aqueous layer was acidified with 1M aqueous HCl (10 mL) to pH 2 and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound (1.41 g) as an off-white solid. The crude product was used in the next step without purification.