Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH:7]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH2:8][CH2:9][CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])(=[O:5])[CH3:4].[H][H].Br[CH2:28][C:29]#[C:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35].Cl>O.CN(C)C=O.C1C=CC=CC=1>[C:3]([O:6][CH:7]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH2:8][CH2:9][CH2:10][N:11]([CH2:28][C:29]#[C:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[S:12]([CH3:15])(=[O:14])=[O:13])(=[O:5])[CH3:4]
Reactant: CC(=O)OC(CCCNS(C)(=O)=O)COc1ccc(F)cc1
Reactant: COC(=O)CCCC#CCBr
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)CCCC#CCN(CCCC(COc1ccc(F)cc1)OC(C)=O)S(C)(=O)=O
Temperature: 25 °C

Procedure:
A stirred suspension of sodium hydride (57%) (.91 g., 0.022 mole) in a solvent mixture of benzene (50 ml.) and dimethylformamide (50 ml.) is treated, over 30 minutes, with N-[4-acetoxy-5-(4-fluorophenoxy)pentyl] -methanesulfonamide (6.5 g., 0.02 mole). This mixture is heated at 60° C. until evolution of hydrogen ceases, then cooled to room temperature. At this temperature is added methyl 7-bromo-5-heptynoate (4.3 g., 0.02 mole) and the reaction is heated at 90° C. for 3 hours. The reaction is poured into water (200 ml.), neutralized with hydrochloric acid and extracted with ethyl acetate (2 × 100 ml.). The ethyl acetate layer is washed with brine, dried over sodium sulfate, then concentrated in vacuo. The product is purified by chromatography over silica gel using 5% methanol in chloroform to elute. Evaporation of the appropriate fractions affords the subject compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:37]=[CH:36][C:17]([O:18][CH2:19][C:20]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])([OH:27])[CH2:21][N:22]4[CH:26]=[N:25][CH:24]=[N:23]4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:38]1(=O)[O:43][C:41](=[O:42])[CH2:40][CH2:39]1>C(O)(=O)C>[Cl:35][C:29]1[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:28]=1[C:20]([OH:27])([CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)[CH2:19][O:18][C:17]1[CH:36]=[CH:37][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([N:1]4[C:41](=[O:42])[CH2:40][CH2:39][C:38]4=[O:43])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Reactant: O=C1CCC(=O)O1
Solvent: CC(=O)O
Product: O=C1CCC(=O)N1c1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Yield: 71.8 %

Procedure:
A solution of 3-(4-[4-(4-aminophenyl)piperazin-1-yl]phenoxy)-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (see Preparation 1) (0.2 g, 0.37 mmole) and succinic anhydride (0.05 g, 0.5 mmole) in acetic acid (3 ml) was heated under reflux for 4 hours. The solution was cooled, the solvent removed by concentration under reduced pressure and the resulting gum triturated with isopropanol to provide a solid (0.165 g). Purification of this solid material by flash chromatography on silica gel eluting with methylene chloride (90):isopropanol (10):acetic acid (1) yielded, after collection and evaporation of appropriate fractions, the desired product, m.p. 212°-216° (0.072 g, 31%).
Reaction SMILES: C([O:8][C:9](=[O:37])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:36])[CH2:16][CH2:17][C:18](=[O:35])[C@@H:19]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.CO.[Pd]>[C:21]1([CH2:20][C@H:19]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:18](=[O:35])[CH2:17][CH2:16][C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([OH:37])=[O:8])=[O:36])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)O
Yield: 89.9 %

Procedure:
To a stirred solution of the benzyl ester 10 (100 mg, 0.1968 mmol) in dry EtOAc-MeOH (3:1 ratio) (10 mL) was added 10% Pd/C (50 mg) and the resulting mixture stirred at room temperature under 1 atmosphere of hydrogen for 24 h. Filtration of the black Pd residue and evaporation of the filtrate gave a crude residue. Column chromatography on silica gel elution with 20% MeOH-EtOAc afforded (5S)-6-phenyl-5-[(tert-butyloxycarbonyl)-amino]-4-oxo-hexanoyl-L-proline 11a as a pale colourless oil (74 mg, 90%); Rf 0.23 (20% MeOH-EtOAc); IR (liquid film) ν 1720 (CO), 3000 (broad, COOH) cm−1; 1H NMR (300 MHz, CDCl3) δH 1.39 (9H, s, (CH3)3), 2.04 (2H, m, —CH2—), 2.44 (1H, br-s, —COOH), 2.62 (4H, m,), 2.94 (3H, m), 3.16 (1H, m), 3.60 (2H, m, —CH2N—), 4.52 (2H, m, 2×—CH—), 5.08 (1H, m, —NH—) and 7.14-7.35 (5H, m, Ar—H); 13C NMR (75 MHz, CDCl3) δC 21.0, 22.6, 24.7, 28.0, 29.2, 30.9, 31.4, 34.6, 46.9, 58.7, 60.4, 126.8, 127.0, 128.5, 128.7, 129.5, 136.4, 155.3, 171.8, 173.7, 207.5 and 208.0; HRMS m/z calcd for C22H30N2O6 (M+) 418.21734, found 418.21039.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.[CH2:9]1[CH2:15][S:12](=[O:14])(=[O:13])[O:11][CH2:10]1>O1CCCC1>[CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][CH2:10][CH2:9][CH2:15][S:12]([OH:14])(=[O:13])=[O:11])[CH2:4][CH2:3]1
Reactant: CC1CCC(N)CC1
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: CC1CCC(NCCCS(=O)(=O)O)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-methylcyclohexylamine (97% cis and trans isomers, 11.0 g, 97.4 mmol) in tetrahydrofuran (70 mL) was slowly added a solution of 1,3-propane sultone (11.5 g, 92.8 mmol) in THF (20 mL). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with THF (50 mL) and acetone (50 mL). The solid was suspended EtOH. The suspension was stirred at room temperature for 5 minutes. The solid product was collected by filtration, washed with EtOH (50 mL), and dried in a vacuum oven (50° C.), to afford compound DR (16.1 g, 75%). 1H NMR (D2O, 500 MHz) δ ppm 3.08 (m, 2.5H), 2.93 (m, 0.5H), 2.87 (m, 2H), 1.99 (m, 4H), 1.64 (m, 3H), 1.47 (m, 1H), 1.24 (m, 2H), 0.88 (m, 1H), 0.78 (m, 3H). 13C NMR (D2O, 125 MHz) δ ppm 57.35, 56.52, 48.16, 18.05, 43.73, 43.30, 32.45, 31.13, 28.92, 28.69, 27.77, 24.55, 21.65, 21.53, 21.20, 18.38. ES-MS 236 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([N:7]1[C:6]2[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methylxanthine (2.882 g) was suspended in N,N-dimethylformamide (40 ml), and potassium carbonate (3 g) and benzyl bromide (2.5 ml) was added thereto. The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate, and washed with 1 N hydrochloric acid. The deposited crystals were collected by filtration and washed with ethyl acetate to give 3.18 g of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:11](=[O:13])[CH2:10][CH:9]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[CH2:8][C:7]=2[NH:6][CH:5]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>CN(C)C=O>[CH3:19][S:20]([N:6]1[C:7]2[CH2:8][CH:9]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[CH2:10][C:11](=[O:13])[C:12]=2[C:4]([CH3:3])=[CH:5]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c[nH]c2c1C(=O)CC(c1cccs1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(S(C)(=O)=O)c2c1C(=O)CC(c1cccs1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
To a suspension of 60% sodium hydride (0.11 g, washed with hexane thrice) in dimethylformamide (10 ml) was added 3-methyl-6-(2-thienyl)-4,5,6,7-tetrahydroindol-4-one (0.60 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of methanesulfonylchloride (0.36 g) in dimethylformamide (2 ml), and the mixture was stirred at the same temperature for 14 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane). The resulting crystals were recrystallized from ethyl acetate-hexane to give colorless crystals of 1-methanesulfonyl-3-methyl-6-(2-thienyl)-4,5,6,7-tetrahydroindol-4-one (0.28 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([C:8]1[CH:13]=[CH:12][C:11]([N:14]=[N:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH2:5][CH2:6][OH:7].[Br:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:26][CH:25]=1>C(Cl)Cl>[Br-:22].[OH:7][CH2:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[C:8]1[CH:9]=[CH:10][C:11]([N:14]=[N:15][C:16]2[CH:21]=[CH:20][N+:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([P:30]([O:34][CH2:35][CH3:36])([O:31][CH2:32][CH3:33])=[O:37])=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)=[CH:12][CH:13]=1
Reactant: CCOP(=O)(OCC)c1ccc(CBr)cc1
Reactant: OCCN(CCO)c1ccc(N=Nc2ccncc2)cc1
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1ccc(C[n+]2ccc(N=Nc3ccc(N(CCO)CCO)cc3)cc2)cc1
Product: [Br-]
Temperature: 60 °C

Procedure:
A mixture of 4-[[4-[N,N-bis(hydroxylethyl)amino]phenyl]azo]pyridine (1) (0.286 g, 1.00 mmol, and 4-(bromomethyl)phenylphosphonate (2) (0.317 g, 1.00 mmol) was dissolved in CH2Cl2 (10 mL). The red mixture was heated under a nitrogen atmosphere at 60° C. for 4 h. The solvent was then removed under high vacuum and the residue was dried under high vacuum overnight. 1H NMR (500 MHz, DMSO-d6): δ 9.07 (d, 2H, JH—H=6 Hz), 8.14 (d, 2H, JH—H=7 Hz), 7.90 (d, 2H, JH—H=9.5 Hz), 7.76-7.80 (m, 2H), 7.62-7.64 (m, 2H), 7.07 (d, 2H, JH—H=9.5 Hz), 5.88 (s, 2H), 4.95-4.97 (m, 2H), 3.99-4.03 (m, 4H), 3.99-4.03 (m, 4H), 3.66-3.72 (m, 8H), 1.22 (t, 3H). 31P NMR (400 MHz, DMSO-d6): δ −18.07 (s, 1P). High resolution EI-MS: Calculated for C26H34N4O5P+, 513.22744. Found, 513.22668.
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[C:4]2[C:12]3([O:16]CCO3)[CH2:11][CH2:10][S:9][C:5]2=[C:6]([CH3:8])[CH:7]=1.C([Li])CCC.[C:23](=[O:25])=[O:24]>O1CCCC1.CCCCCC>[CH3:17][C:3]1[C:2]([C:23]([OH:25])=[O:24])=[CH:7][C:6]([CH3:8])=[C:5]2[C:4]=1[C:12](=[O:16])[CH2:11][CH2:10][S:9]2
Reactant: Cc1cc(Br)c(C)c2c1SCCC21OCCO1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(C(=O)O)c(C)c2c1SCCC2=O
Temperature: -65 °C
Reaction time: 1 h

Procedure:
46.38 g (0.15 mol) of 6-bromo-5,8-dimethylspiro[thiochromane-4,2′-[1,3]dioxolane] were dissolved in 500 ml of tetrahydrofuran and cooled to −65° C. 80 ml (0.2 mol) of 2.5 M n-butyllithium in hexane were subsequently slowly added dropwise such that the temperature did not exceed −55° C. The mixture was stirred for another 1 h, and 90 g of dry ice were then added a little at a time. The solution was subsequently allowed to warm to room temperature, 500 ml of hexane were added and the precipitate was filtered off with suction. The precipitate was taken up in 500 ml of water and made strongly acidic using conc. hydrochloric acid. The mixture was boiled under reflux for 1 h and then allowed to cool, and the precipitated product was filtered off with suction.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11](/[C:14](=[N:18]/[O:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])/[C:15](O)=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:34][C@@H:35]1[C:53](=[O:54])[N:37]2[C:38]([C:50]([OH:52])=[O:51])=[C:39]([CH2:42][O:43][C:44](=[O:49])[CH2:45][C:46](=[O:48])[CH3:47])[CH2:40][S:41][C@H:36]12>ClCCl>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11](/[C:14](=[N:18]/[O:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])/[C:15]([NH:34][C@@H:35]2[C:53](=[O:54])[N:37]3[C:38]([C:50]([OH:52])=[O:51])=[C:39]([CH2:42][O:43][C:44](=[O:49])[CH2:45][C:46](=[O:48])[CH3:47])[CH2:40][S:41][C@H:36]23)=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1nsc(NC(=O)OC(C)(C)C)n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCC(=O)OC(C)(C)C)c3nsc(NC(=O)OC(C)(C)C)n3)[C@H]2SC1
Reaction time: 0.33 h
Yield: 103.5 %

Procedure:
To a solution of 13 g of 2-(tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2(Z)-(tert-butoxycarbonylmethoxyimino)acetic acid in 100 ml of dichloromethane, 7 g of phosphorus pentachloride is added and the mixture is stirrred for 20 minutes under ice-cooling. The reaction mixture is evaporated to dryness and to the residue is added hexane and the solvent is evaporated off again. The residue is dissolved in 5 ml of dichloromethane and the solution is added under ice-cooling to a solution prepared by allowing 10 g of 7β-amino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid and 16 g of N,O-bistrimethylsilylacetamide to react in 200 ml of dichloromethane at room temperature for one hour. The mixture is stirred at the same temperature for one hour and the solvent is then evaporated under reduced pressure. The residue is dissolved in 300 ml of ethyl acetate and the solution is washed with water and then dried over anhydrous magnesium sulfate. Then, the solvent is evaporated off and the residue is triturated with hexane. Insoluble substance is collected by filtration to give 23 g of 7β-[2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2(Z)-(tert-butoxycarbonylmethoxyimino)acetamido]-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][NH:6][C:7](=[O:11])[O:8][CH2:9][CH3:10].Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([N+:25]([O-:27])=[O:26])=[CH:18][C:17]=1[C:28]([F:31])([F:30])[F:29].[H-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][N:6]([C:16]1[C:17]([C:28]([F:30])([F:31])[F:29])=[CH:18][C:19]([N+:25]([O-:27])=[O:26])=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[C:7](=[O:11])[O:8][CH2:9][CH3:10]
Reactant: CCOC(=O)NCc1cccc(Cl)c1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1cccc(Cl)c1)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Yield: 9.4 %

Procedure:
Ethyl 3-chlorobenzylcarbamate (720.3 mg) and 2-chloro-3,5-dinitrobenzotrifluoride (829.1 mg) were dissolved in tetrahydrofuran (20 ml), and to the solution was added sodium hydride (147.1 mg). The reaction mixture was heated at reflux for 1.5 hours. After allowing to cool, to the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (75 g, hexane:ethyl acetate=10:1) to give the title compound (129.5 mg, 9%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:16]#[C:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Nc1cccc(Br)n1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Nc1cccc(C#Cc2ccccc2)n1

Procedure:
A solution of 2-amino-6-bromopyridine (200 mg, 1.16 mmol), 1-phenylacetylene (142 mg, 1.39 mmol), bis(triphenylphosphine) palladium (II) chloride (14 mg, 0.02 mmol), and CuI (2 mg, 0.01 mmol) in 2 mL triethylamine was stirred at 60° C. in a sealed tube for 18 hours. The reaction was cooled and concentrated in vacuo to a dark oil. The oil was purified by gravity column chromatography over silica gel with 2% methanol/chloroform to give the desired product as a brown oil. 400 Mhz H1NMR (CDCl3): 4.57(br s, 2H), 6.49(d, 1H), 6.93(d, 1H), 7.38(m, 3H), 7.41(t, 1H), 7.58(d, 1H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:8]([O:15][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)O1
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O)CCC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
Succinic anhydride (30 g, 300 mmole) was dissolved in methylene chloride (300 ml). To the solution were added benzyl alcohol (10.2 ml, 100 mmole), 4-dimethylaminopyridine (1.22 g, 10 mmole) and pyridine (48 ml). After 3 hours the reaction mixture was poured in to citric acid aqueous solution. The organic phase was concentrated to small volume and sodium hydrogen carbonate and water were added. Then mixture was stirred for 30 min. The aqueous phase was collected, and to it was added citric acid aqueous solution. The product precipitated out, was collected and dried. 15.3 g. 1H-NMR (CDCl3): 7.50 (m, 5H), 5.25 (s, 2H), 2.68 (m, 4H).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:8]([O:20][CH3:21])=[CH:9][CH:10]=[C:11]([C:16](OC)=[O:17])[C:12]=2[C:13](=O)[CH:14]=1)=[O:4].[NH2:22][NH2:23]>CCO>[CH3:21][O:20][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[O:17])[NH:23][N:22]=[C:13]3[CH:14]=[C:5]([C:3]([OH:2])=[O:4])[NH:6][C:7]=1[C:12]=23
Reactant: NN
Reactant: COC(=O)c1cc(=O)c2c(C(=O)OC)ccc(OC)c2[nH]1
Solvent: CCO
Product: COc1ccc2c(=O)[nH]nc3c2c1NC(C(=O)O)=C3
Temperature: 68 °C

Procedure:
6-Methoxy-3-oxo-2,7-dihydro-3H-pyrido[4,3,2-de]phthalazine-8-carboxylic acid hydrozide (39) To a suspension of 38 (0.45 g, 1.54 mmol) in EtOH (20 mL) was added hydrazine (1 mL) at room temperature. The reaction mixture was heated at 68° C. for 1.5 h and then cooled to room temperature. The resulting precipitate was filtered and washed with Et2O to afford a white solid (39, 0.31 g, 74%). 1H NMR (DMSO-d6, 300 MHz) δ 10.5 (br s, 1H), 9.0 (br s, 1H), 7.15-7.25 (m, 2H), 7.1 (br s, 1H), 6.8 (br s, 1H), 4.90 (br s, 2H), 4.03 (s, 3H). Mp: 305-307° C.; Anal. Calcd for C12H11N5O3.(0.75H2O): C, 50.26; H, 4.39; N, 24.42. Found: C, 50.33; H, 4.46; N, 22.04.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]([O:27]C)=O)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][CH2:30][Mg+].[Br-]>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:1]([N:20]1[CH:24]=[C:23]([C:25]2([OH:27])[CH2:30][CH2:29]2)[N:22]=[CH:21]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC[Mg+]
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: OC1(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 4 %

Procedure:
A solution of methyl 1-trityl-1H-imidazole-4-carboxylate (11.0 g, 29.9 mmol) and Ti(OiPr)4 (12.37 mL, 41.8 mmol) in THF (3 mL) was treated dropwise with a 1M solution of EtMgBr (76 mL, 76 mmol) to maintain the temperature below 35° C. The mixture was then stirred at RT for 4 h, and then poured onto H2O. The precipitate was filtered off, and the filtrate was extracted with AcOEt. The combined org. layers were dried over Na2O4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, AcOEt/heptane 30:70 to 100:0) gave the title compound (440 mg). UPLC-MS: MS 367.3 (M+H+); UPLC rt 1.01 min.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.IC.[H-].[Na+].[C:30](OCC)(=O)C>O1CCCC1.O>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:30])[C:9]([OH:11])=[O:10])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(-c2ccccc2)cc1)C(=O)O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 120 h

Procedure:
3-(1,1′-Biphenyl-4-yl)-2-tert-butoxycarbonylaminopropionic acid (5.0 g; 14.66 mmol) was dissolved in dry tetrahydrofuran (45 mL). Iodomethane (7.3 mL; 117.3 mmol) was added and the reaction mixture was cooled to 0° C. Sodium hydride (1.75 g; as 44.0 mmol) was added and the reaction mixture was stirred for 5 days at room temperature. Ethyl acetate (50 mL) was added and water (20 mL) was added dropwise. The solvent was removed in vacuo and the residue was dissolved in an aqueous solution of sodium hydrogen carbonate (saturated; 50 mL) and washed with diethyl ether (30 mL). The aqueous phase was acidified to pH 3 using citric acid (5%) and extracted with ethyl acetate (3×50 mL). The organic phase was washed with an aqueous solution of sodium thiosulfate (5%; 75 mL) and dried (magnesium sulfate). The solvent was removed in vacuo to afford 3.85 g of (2R)-3-(1,1′-biphenyl-4-yl)-2-(N-tert-butoxycarbonyl-N-methylamino)propionic acid.
Reaction SMILES: [CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[C:29](=[O:30])[CH2:28][C@H:27]6[CH2:31][NH:32][CH2:33][C@H:26]6[CH2:25]5)=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:39]=O.[Na]>C1COCC1>[CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[C:29](=[O:30])[CH2:28][C@H:27]6[CH2:31][N:32]([CH3:39])[CH2:33][C@H:26]6[CH2:25]5)=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@H]5CNC[C@@H]5CC4=O)cn3)nc2n1C1CCCCCC1
Reactant: C=O
Agent: [Na]
Solvent: C1CCOC1
Product: CN1C[C@@H]2CC(=O)N(c3ccc(Nc4ncc5cc(C(=O)N(C)C)n(C6CCCCCC6)c5n4)nc3)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.6 %

Procedure:
To a solution of 7-cycloheptyl-N,N-dimethyl-2-(5-((3aS,7aR)-6-oxotetrahydro-1H-pyrrolo[3,4-c]pyridin-5(6H,7H,7aH)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (from example 89, enantiomer-2) (66 mg, 0.128 mmol, 1 eq) in THF (2.0 mL) was added 37% aqueous solution of formaldehyde (0.048 mL, 0.639 mmol, 5 eq). The reaction mixture was stirred at room temperature for 5 minutes. Solid sodium triacetoxyhydroborate (81 mg, 0.383 mmol, 3 eq was added into the mixture. The reaction was stirred for 10 more minutes and quenched with a drop of TFA and naturalized with ammonia in methanol. The residue was concentrated under vacuum and purified by column chromatography (NH3/MeOH/CH2Cl2) to provide 7-cycloheptyl-N,N-dimethyl-2-(5-((3aS,7aR)-2-methyl-6-oxotetrahydro-1H-pyrrolo[3,4-c]pyridin-5(6H,7H,7aH)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (67 mg) in quantitative yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (s, 1H), 8.63 (d, J=9.09 Hz, 1H), 8.27 (s, 1H), 8.24 (d, J=2.53 Hz, 1H), 7.67 (dd, J1=9.09, J2=2.53 Hz, 1H), 6.44 (s, 1H), 4.73 (s, 3H), 4.52 (m, 1H), 3.83 (dd, J1=13.14, J2=4.04 Hz, 1H), 3.65 (dd, J1=13.14, J2=4.04 Hz, 1H), 3.17 (s, 6H), 2.91-2.51 (m, 7H), 2.36 (m, 4H), 2.01 (m, 2H), 1.87 (m, 2H), 1.79-1.51 (m, 5H); HRMS m/z 531.3219 (M+H)+.