Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].C(N)CN.[C:7]1([C:13]#[C:14][C:15]([OH:17])=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H][H]>C(O)C.O.O.O.O.C([O-])(=O)C.[Ni+2].C([O-])(=O)C>[C:7]1(/[CH:13]=[CH:14]\[C:15]([OH:17])=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)C#Cc1ccccc1
Reactant: [H][H]
Agent: [Ni+2]
Agent: CC(=O)[O-]
Agent: [BH4-]
Solvent: O
Solvent: CCO
Solvent: NCCN
Product: O=C(O)/C=C\c1ccccc1
Reaction time: 5 h
Yield: 68.8 %

Procedure:
Nickel (II) acetate tetrahydrate (0.16 g, 0.00063 moles) was dissolved in ethanol (6.3 mL) and placed under hydrogen atmosphere. The green solution was stirred rapidly while sodium borohydride (0.024 g, 0.00063 moles) in ethanol (0.63 mL) was added. The deep purple solution was then treated with ethylene diamine (0.42 mL, 0.0063 moles) followed by 3-phenylpropynoic acid (0.73 g, 0.005 moles). The reaction was stirred under hydrogen for 5 hours. The hydrogen was displaced with nitrogen and the suspension was filtered through diatomaceous earth to remove the catalyst. The filtrate was concentrated in vacuo. The residue was taken up in chloroform and water, and concentrated hydrochloric acid was added to acidify the aqueous layer. The layers were separated and the acidic layer was extracted three times more with chloroform. The organic layers were combined and concentrated. The material was purified by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of 10-40% acetonitrile and 0.25% aqueous trifluoroacetic acid as the eluent to give a white solid (0.51 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([F:32])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.[CH3:33][N:34]([CH3:40])[C:35](=[O:39])[C:36](O)=[O:37].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:32][C:5]1[CH:4]=[N:3][C:2]([NH:1][C:36](=[O:37])[C:35]([N:34]([CH3:40])[CH3:33])=[O:39])=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:31])[C:12](=[O:13])[N:14]3[CH2:15][CH2:16][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:18][CH2:19]3)[C:6]=12
Reactant: Nc1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Reactant: CN(C)C(=O)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C(=O)Nc1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.9 %

Procedure:
1-(7-amino-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (100 mg, 0.23 mmol) was dissolved in DMF (2 mL) and treated with N,N-dimethyloxamic acid (27 mg, 0.23 mmol), Hunig's base (0.14 mL, 0.8 mmol) and TBTU (81 mg, 0.25 mmol). The reaction mixture was stirred at rt for 18 h. Solvent was removed in vacuum and water was added. A solid precipitated out and it was collected by filtration, dissolved in DMF and purified using reverse phase prep HPLC to afford the title compound as a pale yellow solid (11 mg). 1HNMR (500 MHz, DMSO-D6) δ 8.47 (s, 1H), 8.16 (s, 1H), 7.70-7.50 (m, 5H), 5.76 (m, 1H), 4.10-3.10 (m, 6H), 3.16 (s, 6H). LCMS: m/e 535 (M+H)+, ret time 1.33 min (method 1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:23])[CH:3]=1>CO.[Pd]>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:23])[CH:3]=1
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(N)cc1
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of 6.81 g (21.0 mmol) of the product of Step A dissolved in 75 mL methanol in a high pressure reaction vessel was added 0.3 g 5% palladium on carbon. The resulting suspension was pressurized to 40 psi with H2 and shaken for 2 hours. The solution was filtered through a pad of celite and the filtrate concentrated to a gray-green oil which crystallized on standing. The crude material was flash chromatographed with 50% ethyl acetate/hexane and 3% methanol/ethyl acetate to yield 5.0 g (85%) of the title compound.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C@@H:11]([OH:28])[C@@H:12]([OH:27])[C@H:13]([CH3:26])[C@H:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@@H:15]([CH3:17])[CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C(C)=CC=CC=1C.[Si:37](OS(C(F)(F)F)(=O)=O)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38].CO>C(Cl)Cl>[C:1]1([S:7]([C:10]2[C@@H:11]([OH:28])[C@@H:12]([O:27][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C@H:13]([CH3:26])[C@H:14]([O:18][Si:19]([C:22]([CH3:23])([CH3:25])[CH3:24])([CH3:20])[CH3:21])[C@@H:15]([CH3:17])[CH:16]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C[C@H]1[C@H](O)[C@H](O)C(S(=O)(=O)c2ccccc2)=C[C@H](C)[C@H]1O[Si](C)(C)C(C)(C)C
Solvent: CO
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)[C@H](O)C(S(=O)(=O)c2ccccc2)=C[C@H](C)[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Compound 39 (77 mg, 0.18 mmol) was dissolved in dry methylene chloride (2.0 mL), and cooled to −78° C. To this cold solution were added 2,6-lutidine (32 μL, 0.27 mmol), followed by TBSOTf (50 μL, 0.22 mmol) under nitrogen. After stirring for 2 h at −78° C. (the reaction was monitored by TLC until completionusing a mixture of 1:1 EA/hexanes), 0.2 mL of methyl alcohol was then added to quench the excess of TBSOTf. The resulting solution was concentrated via rotary evaporation and the residue was purified by flash column chromatography (ethyl acetate/hexane, 1:5) to afford 97 mg (99% yield) of 52 as a white solid. mp 81.0-83.0° C.; [α]20D=+38.8 (c=1.3, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.83-7.86 (m, 2H), 7.50-7.71 (m, 3H), 7.37 (d, J=7.8 Hz, 1H), 4.29 (br s, 1H), 3.81 (d, J=4.5 Hz, 1H), 3.56 (dd, J=2.1 Hz, 8.7 Hz, 1H), 2.79 (m, 1H), 2.53 (br s, 1H), 2.45 (m, 1H), 1.22 (d, J=7.2 Hz, 3H), 0.99 (d, J=7.2 Hz, 3H), 0.88 (s, 9H), 0.81 (s, 9H), 0.077 (s, 3H), 0.052 (s, 3H), −0.14 (s, 3H), −0.35 (s, 3H). 13C NMR (CDCl3, 75 MHz) δ 148.8, 139.6, 139.5, 133.5, 129.4, 128.1, 77.7, 73.3, 70.6, 40.3, 36.3, 26.1, 18.3, 18.1, 17.6, 17.5, −4.11, −4.54, −4.61, −4.90. LRMS (CI): m/z 541 [M+H]+; HRMS (CI) calculated for C27H48O5SSi2, 541.2839; found, 541.2834.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:20])=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:6]2)#[N:2].Cl.[NH2:22][OH:23].C(=O)(O)[O-].[Na+]>C(O)C>[OH:23][NH:22][C:1](=[NH:2])[C:3]1[C:4]([CH3:20])=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:7][CH2:6]2
Reactant: Cc1c(C#N)ccc2c1CCN(C(=O)OC(C)(C)C)C2
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1c(C(=N)NO)ccc2c1CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
1,1-Dimethylethyl 6-cyano-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 16; 404 mg; 1.48 mmol) was stirred overnight at 80° C. with hydroxylamine hydrochloride (619 mg; 8.90 mmol) and sodium bicarbonate (748 mg; 8.9 mmol) in ethanol (10 ml). Further sodium bicarbonate (400 mg) and hydroxylamine hydrochloride (300 mg) were added, and heating continued for ca. 8 h. The mixture was cooled to room temperature, and the resulting solid removed, washed with ethanol, and dried under high vacuum to give the title compound as a white solid (431 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3([CH2:13][CH2:12][CH2:11][CH2:10]3)[O:8][B:7]([OH:14])[C:6]=2[CH:15]=1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3([CH2:13][CH2:12][CH2:11][CH2:10]3)[O:8][B:7]([OH:14])[C:6]=2[CH:15]=1
Reactant: Cc1ccc2c(c1)B(O)OC21CCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: OB1OC2(CCCC2)c2ccc(CBr)cc21
Temperature: 25 °C
Yield: 71.2 %

Procedure:
To a solution of 6-methyl-1H-spiro[benzo[c][1,2]oxaborole-3,1′-cyclopentan]-1-ol (1.2 g, 6.0 mmol) in CCl4 (10 mL) under nitrogen was added NBS (1.07 g, 6.0 mmol) and BPO (145 mg, 0.6 mmol). The mixture was heated at reflux for 2 h under the light from a Sun lamp, and then it was cooled to rt, washed with aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified on column chromatography to provide the product (1.2 g, yield 71.7%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@H:14]1[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=2[F:26])[C@:17]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])([C:27]#[N:28])[C@H:16]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:15]1)=[O:13])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH:14]1[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=2[F:26])[C:17]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])([C:27]#[N:28])[CH:16]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:15]1)=[O:13]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NCCCNC(=O)OC(C)(C)C)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCCCN)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F

Procedure:
Rac (3-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester (815 mg) was treated with 30% TFA/methylene chloride (10 mL) overnight. Removal of solvent and freeze drying of the residue give a white powder. 800 mg.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH:9]=[C:10]4[C@:15]3([CH3:16])[CH:14]=[CH:13][C@H:12]([OH:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[OH:21].[CH2:22](COC)OC.C(I)I>CCOCC.[Cu].[Zn]>[CH2:22]1[C@@H:13]2[C@H:12]([OH:20])[CH2:11][C:10]3[C@:15]([CH3:16])([C@H:14]12)[C@@H:17]1[C@H:7]([C@H:6]2[C@@:2]([CH2:19][CH2:18]1)([CH3:1])[C@@H:3]([OH:21])[CH2:4][CH2:5]2)[CH2:8][CH:9]=3
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)C=C[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: COCCOC
Agent: [Cu]
Agent: [Zn]
Solvent: ICI
Solvent: CCOCC
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)[C@H]5C[C@H]5[C@@]43C)[C@@H]1CC[C@@H]2O
Temperature: 25 °C

Procedure:
To a stirred solution of 1,5-androstadiene-3β,17β-diol in a mixture of dry ether and glyme is added zinc-copper couple and methylene iodide. This reaction mixture is refluxed for 4 hours, cooled to room temperature, diluted with ether and filtered. The filtrate is washed with aqueous sodium chloride, water and dried over anhydrous magnesium sulfate. The ether is removed under reduced pressure and the residue crystallized from acetone-hexane to yield 1β,2β-methylene-5-androstene-3β,17β-diol.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][Si](C)(C)C)[CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:21]1[CH2:24][CH:23]([NH:25][C:26]([CH2:28][NH:29][C:30](=[O:41])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)=[O:27])[CH2:22]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[C:15]([C:11]1[CH:10]=[C:9]([C:2]2([OH:1])[CH2:7][CH2:6][CH:5]([N:21]3[CH2:24][CH:23]([NH:25][C:26]([CH2:28][NH:29][C:30](=[O:41])[C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=4)=[O:27])[CH2:22]3)[CH2:4][CH2:3]2)[CH:14]=[CH:13][CH:12]=1)#[CH:16]
Reactant: C[Si](C)(C)C#Cc1cccc(C2(O)CCC(=O)CC2)c1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C#Cc1cccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-hydroxy-4-(3-trimethylsilanylethynyl-phenyl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4 followed by a TBAF work-up using the procedure described in Step D of Example 40.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:3]1=[O:17].[Br:18]NC(=O)CCC(N)=O>CN(C=O)C>[Br:18][C:7]1[NH:8][C:9]2[C:10](=[O:11])[N:2]([CH3:1])[C:3](=[O:17])[N:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:5]=2[N:6]=1
Reactant: CCCCCn1c(=O)n(C)c(=O)c2[nH]cnc21
Reactant: NC(=O)CCC(=O)NBr
Solvent: CN(C)C=O
Product: CCCCCn1c(=O)n(C)c(=O)c2[nH]c(Br)nc21
Reaction time: 18 h
Yield: 12.7 %

Procedure:
1-methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (0.06 g, 0.25 mmol) was dissolved in DMF (2 ml) and N-bromosuccinamide (0.045 g, 0.25 mmol) added. The mixture was stirred for 18 h, concentrated and the crude purified by eluting through an aminopropyl SPE (5 g) with first methanol then 5% acetic acid/methanol to elute product. The product was further purified by mass directed auto prep to yield the title compound as a white solid (0.01 g, 12%). NMR δH (400 MHz, d6-DMSO) 0.86 (t, 3H, J=7 Hz), 1.21-1.35 (m, 4H), 1.59-1.68 (m, 2H), 3.22 (s, 3H), 3.91 (t, 2H, J=7.5 Hz), 14.39 (br. s, 1H); m/z 315, 317 [MH+].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]([C:38]#[N:39])[NH:16][C:17]([C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]2[NH:25][C:26]([C:28]2[N:29]([CH3:37])[C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:38]([CH:15]([NH:16][C:17]([C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]([C:28]1[N:29]([CH3:37])[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[O:18])[CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)#[N:39]
Reactant: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)NC(C#N)CC2CCN(C(=O)OC(C)(C)C)CC2)cc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)NC(C#N)CC2CCNCC2)cc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.4 %

Procedure:
To a solution of 4-[2-cyano-2-({(1R,2S)-2-[(1-methyl-1H-indole-2-carbonyl)-amino]-cyclohexanecarbonyl}-amino)-ethyl]-piperidine-1-carboxylic acid tert-butyl ester (1.20 g, 2.24 mmol) in 20 mL of CH2Cl2, was added TFA (4.0 mL, 52 mmol). The reaction mixture was stirred at ambient temperature for 4 hours, concentrated, poured into an aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried with sodium sulfate, and concentrated to give 541 mg (55%) of 1-methyl-1H-indole-2-carboxylic acid {(1S,2R)-2-[(cyano-piperidin-4-ylmethyl-methyl)-carbamoyl]-cyclohexyl}-amide as a pale-yellow amorphous material. MS: 436 (M+H+).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[NH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:30]1[CH2:31][CH2:32][CH:27]([NH:26][C:4]([C:6]2[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]3[C:15]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)=[O:5])[CH2:28][CH2:29]1
Reactant: NC1CCOCC1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccncc3)noc2C)nn1
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)NC2CCOCC2)nn1
Yield: 34 %

Procedure:
As described for example 69, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester (100 mg, 0.29 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (39 mg, 34%) which was obtained as a white foam. MS: m/e=396.4 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:22](=[CH:23][CH:24]=1)[O:21][C:8]1([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH2:7][C:6]2=[O:25])#[N:2].[BH4-].[Na+].[NH4+].[Cl-]>CCO.C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:22](=[CH:23][CH:24]=1)[O:21][C:8]1([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH2:7][CH:6]2[OH:25])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(C#N)ccc1O2
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)c1cc(C#N)ccc1O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 15 g of tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate in 250 mL of EtOH-THF(1:4) at 0° C. was added NaBH4 portionwise, and the reaction mixture was allowed to warm up to rt. After stirring for 1 h, NH4Cl aqueous was added to the reaction mixture and the aqueous mixture was extracted with AcOEt twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in reduced pressure to give the intended compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:3]([CH:12]([CH3:30])[C:13](=[O:29])[C:14]1[CH:28]=[CH:27][C:17]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:20][C:16]=2[CH:15]=1)([C:8]([O:10]C)=[O:9])[C:4]([O:6]C)=[O:5])[CH3:2].[OH-].[Li+]>O1CCOCC1.O>[CH2:1]([C:3]([CH:12]([CH3:30])[C:13](=[O:29])[C:14]1[CH:28]=[CH:27][C:17]2[N:18]=[C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:20][C:16]=2[CH:15]=1)([C:4]([OH:6])=[O:5])[C:8]([OH:10])=[O:9])[CH3:2]
Reactant: CCC(C(=O)OC)(C(=O)OC)C(C)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCC(C(=O)O)(C(=O)O)C(C)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
660 mg (1.13 mmol) dimethyl 2-ethyl-2-[1-methyl-2-oxo-2-(2-phenyl-benzoxazol-6-yl)-ethyl]-malonate are dissolved in 20 ml dioxane. Then 170 mg (7.10 mmol) lithium hydroxide, dissolved in 5 ml of water, are added and the mixture is stirred overnight at RT. The reaction mixture is extracted with DCM, the aqueous phase is acidified and extracted again with DCM. Then the org. phase is dried and the solv. is completely eliminated by rotary evaporation i.V. The residue is separated by RP-HPLC (basic).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][C:7](=[O:13])[CH:6]=[CH:5]2.[CH:14]([NH:16][NH:17][CH:18]=O)=O>>[N:16]1[N:17]=[CH:18][N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[C:10]([CH3:12])[CH:11]=2)[NH:8][C:7](=[O:13])[CH:6]=[CH:5]3)[CH:14]=1
Reactant: Cc1cc(N)cc2ccc(=O)[nH]c12
Reactant: O=CNNC=O
Product: Cc1cc(-n2cnnc2)cc2ccc(=O)[nH]c12

Procedure:
A mixture of 6-amino-8-methyl-2-(1H)-quinolone (0.485 g) and 1,2-diformylhydrazine (0.245 g) was stirred and heated in a melt at 200° for 1 hour. The residue was then triturated with hot isopropanol, cooled and filtered and the solid residue was recrystallized from chloroform-isopropanol to afford 6-(1,2,4-triazol-4-yl)-8-methyl-2-(1H)-quinolone 0.25H2O, m.p. 369°-371° (0.112 g).
Reaction SMILES: N[C:2]1C=CC(CC(N)=O)=CC=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.[S:23](=[O:27])(=[O:26])([OH:25])[OH:24]>CO>[S:23]([OH:27])([OH:26])(=[O:25])=[O:24].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([O:22][CH3:2])=[O:21])=[CH:17][CH:18]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: NC(=O)Cc1ccc(N)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)Cc1ccc(N)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
The 4-aminophenylacetamide used in this example was obtained according to patent literature WO 02/08247 A2 or WO 03/051909 A2. Procedure was as follows: Methanol (200 mL) was charged to 4-aminophenylacetic acid (Aldrich) (25 g, 0.165 mol). Sulfuric acid (18 mL concentrated, 0.648 mol) was added maintaining the temperature <20° C. The mixture was then refluxed for one hour and concentrated by distillation at atmospheric pressure until the volume of 140 mL. The mixture was then cooled to 50° C. and tert-buthyl methyl ether (300 mL) was added maintaining the temperature above 45° C. The mixture was gradually cooled to 0-5° C. and held at this temperature for 1 hour. The resultant crystalline product was isolated by filtration and washed with cold methanol: tert-butyl methyl ether (20 mL: 55 mL) and cold tert-butyl methyl ether and then dried under vacuum to give methyl 4-aminophenylacetate hydrogensulfate (35.3 g, 80% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1[O:22][CH2:23][CH:24]1[CH2:26][CH2:25]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.O.[BH4-].[Na+]>C1COCC1>[CH:24]1([CH2:23][O:22][C:14]2[CH:15]=[C:16]([CH2:17][OH:18])[CH:20]=[CH:21][C:13]=2[N:8]([S:9]([CH3:12])(=[O:11])=[O:10])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)O)cc1OCC1CC1)S(C)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1ccc(CO)cc1OCC1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)-benzoic acid (for reference procedure see Example 18, WO 2010/089107, which is incorporated herein by reference in its entirety) (200 mg, 0.519 mmol) was dissolved in THF (10.5 ml), then CDI was added (154 mg, 0.95 mmol). The mixture was stirred at RT for 2 days, then H2O (1.75 ml) and NaBH4 (36 mg, 0.95 mmols) were added. The solvent was removed by evaporation under vacuum. The crude was dissolved in EtOAc (80 ml) and washed with water. The organic phase was dried over Na2SO4 and evaporated under vacuum to yield 200 mg of the desired product.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:15][C:8]([CH2:9][S:10][CH2:11][CH2:12]SC)=[CH:7][CH:6]=1)[CH3:3].[N+:16]([CH:19]=[C:20]([NH:22][CH:23]([C:25]1[CH2:30][CH:29]=[CH:28][CH2:27][CH:26]=1)[CH3:24])[NH2:21])([O-:18])=[O:17]>>[CH3:1][N:2]([CH2:4][C:5]1[O:15][C:8]([CH2:9][S:10][CH2:11][CH2:12][NH:21][C:20]([NH:22][CH:23]([C:25]2[CH2:30][CH:29]=[CH:28][CH2:27][CH:26]=2)[CH3:24])=[CH:19][N+:16]([O-:18])=[O:17])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CSCCSCc1ccc(CN(C)C)o1
Reactant: CC(NC(N)=C[N+](=O)[O-])C1=CCC=CC1
Product: CC(NC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1)C1=CCC=CC1

Procedure:
24.54 grams of 2-[[5-[(dimethylamino)methyl]furfuryl]thio]ethylmethylsulphide are reacted with 41 grams of 2-nitro-N'-(1,4-cyclohexadienyl-2-ethyl)-1,1-ethenediamine at 80° C. for 3 hours. The mixture is cooled and the procedure described in Example 1 is followed. Spectrophotometric analyses confirm the structure of the compound obtained.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[OH-].[Na+].O.[C:12]1([CH3:24])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[S:20](Cl)(=[O:22])=[O:21]>C1(C)C=CC=CC=1>[C:12]1([CH3:24])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[S:20]([O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1)(=[O:21])=[O:22]
Reactant: Cc1ccc(O)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(OS(=O)(=O)c2c(C)cc(C)cc2C)cc1
Reaction time: 1 h

Procedure:
10.8 g of p-cresol is added to a mixture containing 9.17 g of 48% NaOH, 50 ml of water and 50 ml of toluene. To the resulting mixture is added 22.9 g of mesitylenesulfonyl chloride, and reaction is carried out at 60° to 65° C. for 1 hour. After separating the aqueous layer, toluene is removed from the toluene layer by distillation. The resulting desired compound is purified with methanol.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[Cl:8][C:9]1[CH:14]=[C:13]([NH2:15])[N:12]=[C:11]([NH2:16])[N:10]=1>CS(C)=O>[NH2:16][C:11]1[N:12]=[C:13]([NH:15][C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[CH:14]=[C:9]([Cl:8])[N:10]=1
Reactant: CCCCN=C=O
Reactant: Nc1cc(Cl)nc(N)n1
Solvent: CS(C)=O
Product: CCCCNC(=O)Nc1cc(Cl)nc(N)n1
Temperature: 80 °C

Procedure:
8.6 cm3 of n-butylisocyanate was added to a suspension of 5 g of 4-chloro-2,6-diaminopyrimidine in 50 cm3 of DMSO then heated to 80° C. until the starting compound was shown by TLC to have disappeared.