Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[CH2:12]([N:19]=[N+:20]=[N-:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[ClH:1].[CH2:12]([N:19]1[CH:5]=[C:4]([CH2:3][CH2:2][C:6]2[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=2)[N:21]=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#CCCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: Cl
Product: Nc1nc(CCc2cn(Cc3ccccc3)nn2)c[nH]1
Yield: 45.8 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.073 g, 0.423 mmol) was reacted with benzyl azide (0.068 g, 0.509 mmol) following the general procedure for click reactions outlined above to produce 4-[2-(1-Benzyl-1H-[1,2,3]triazol-4-yl)-ethyl]-1H-imidazol-2-ylamine hydrochloride (0.059 g, 46%) as a pale yellow oil. 1H NMR (300 MHz, CD3OD) δ 7.83 (d, 1H), δ 7.37-7.24 (m, 5H), δ 6.44 (d, 1H), δ 5.54 (d, 2H), δ 2.96 (m, 2H), δ 2.83 (m, 2H) ppm; 13C (75 MHz, CD3OD) δ 163.7, 147.3, 146.4, 135.7, 128.8, 128.4, 127.9, 127.8, 126.5, 122.6, 109.1, 53.7, 24.1, 23.9 ppm; HRMS (ESI) calcd for C14H16N6 (M+) 269.1515, found 269.1513.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:26]=1[C:32](=[O:34])[CH3:33])(=O)C.[O:35]1[CH:39]=[CH:38][C:37]2[CH:40]=[C:41]([CH:44]=O)[CH:42]=[CH:43][C:36]1=2>C(O)C.C(O)(=O)C.[C].[Pd]>[C@@H:6]1([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:26]=2[C:32](=[O:34])[CH2:33][CH2:44][C:41]2[CH:42]=[CH:43][C:36]3[O:35][CH2:39][CH2:38][C:37]=3[CH:40]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: O=Cc1ccc2occc2c1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc(O)c2C(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(CCc1ccc2c(c1)CCO2)c1c(O)cccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 78.4 %

Procedure:
2'-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-6'-hydroxyacetophenone (1268 mg) and benzo[b]furan-5-carbaldehyde (911 mg) are treated in the same manner as in Example 1 to give crude 2'-(β-D-glucopyranosyloxy)-6'-hydroxy-3-(5-benzo[b]furanyl)acrylophenone. This product is dissolved in a mixture of ethanol (20 ml) and acetic acid (2 ml), and the mixture is subjected to catalytic hydrogenation by using 10% palladium-carbon (0.5 g) under atmospheric pressure. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. To the residue are added ethyl acetate and water, and the mixture is stirred. The organic layer is collected, washed with a saturated aqueous sodium hydrogen carbonate solution, dried, and evaporated to remove the solvent. The residue is pulverized with chloroform-diisopropyl ether, and the obtained powder is collected by filtration and dried to give 2'-(β-D-glucopyranosyloxy)-6'-hydroxy-3-(2,3-dihydro-5-benzo[b]furanyl)propiophenone (920 mg).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]3[NH:16][C:15]2=[O:23])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].[ClH:26]>CO.O.[C].[Pd]>[ClH:26].[N:14]1([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]2[NH:16][C:15]1=[O:23]
Reactant: O=C1NC2CCCCC2N1C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1NC2CCCCC2N1C1CCNCC1

Procedure:
In this reference example, a solution of 6.1 g of 1-benzyl-4-(octahydro-2H-benzimidazol-2-one-1-yl)-piperidine obtained in the same manner as that of Reference Example 18 and 1 g of 5% palladium carbon in 100 ml of methanol, 100 ml of water and 20 ml of 12 N hydrochloric acid is shaken in the atmosphere of hydrogen under 4 to 5 atmosphere in an autoclave. The shaking is ceased when the absorption of hydrogen has been completed. The reaction mixture is subjected to filtration to remove the catalyst and the filtrate is concentrated. The residue is mixed with 20 ml of isopropanol and stirred to crystallize the reaction product. The crystals are dried and recrystallized from ethanol to obtain 3.9 g of the desired product.
Reaction SMILES: [CH3:1][Si:2]([CH3:48])([CH3:47])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4C([CH:26]=3)=CC=CC=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31][CH:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29][CH2:28]2)[CH:9]=1.C[N:50]1C=C(B2OC(C)(C)C(C)(C)O2)C=N1.N1C2C(=CC=CC=2)C=C(B(O)O)C=1>>[CH3:47][Si:2]([CH3:48])([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:26]=[N:50][N:19]([CH3:20])[CH:18]=3)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:28][CH2:29][CH:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:31][CH2:32]2)[CH:9]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Agent: OB(O)c1cnc2ccccc2c1
Product: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnn(C)c4)c3n2)CC1

Procedure:
Ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate was synthesized in a manner similar to the synthesis of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate, but with N-methyl pyrazole-4-boronic acid pinacol ester substituted for quinoline-3-boronic acid.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][NH2:20])=[CH:17][C:4]1=2.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>C(Cl)Cl>[O:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][NH:20][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:17][C:4]1=2
Reactant: CS(=O)(=O)Cl
Reactant: NCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)NCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Reaction time: 0.75 h
Yield: 49 %

Procedure:
To a solution of 3.5 g (0.014 m), of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethylamine of Example 6 and 1.4 g (0.014 m) of triethylamine in 50 ml of CH2Cl2, 1.6 g (0.014 m) of methanesulfonyl chloride was added dropwise maintaining the temperature between 15°-20° C. The mixture was stirred 45 minutes, then poured into water. The CH2Cl2 layer was separated, washed with water, dried (Na2SO4), filtered and evaporated to give a foamy solid. Recrystallization from approximately 40 ml of toluene gave 2.27 g (49%) of N-(2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethyl)methanesulfonamide, m.p. 104°-106° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[S:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:21][CH:22]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH:29][C@@H:30]([CH2:43][NH2:44])[CH2:31][O:32][C:33]1[C:41]2[NH:40][C:39](=[O:42])[NH:38][C:37]=2[CH:36]=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C)C=O>[OH:29][C@H:30]([CH2:31][O:32][C:33]1[C:41]2[NH:40][C:39](=[O:42])[NH:38][C:37]=2[CH:36]=[CH:35][CH:34]=1)[CH2:43][NH:44][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[S:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:21][CH:22]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(-c4ccccn4)s3)cc2)CC1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=c1[nH]c2cccc(OC[C@@H](O)CNC3CCN(c4ccc(NS(=O)(=O)c5ccc(-c6ccccn6)s5)cc4)CC3)c2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-Pyridin-2-yl-thiophene-2-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example 227) (0.21 g, 0.5 mmol) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) (0.11 g, 0.5 mmol) were mixed in dimethylformamide (10 mL) and then treated with sodium triacetoxyborohydride, (0.16 g, 0.75 mmol) and acetic acid (0.045 g, 0.75 mmol). After stirring at room temperature under a nitrogen atmosphere for one day the mixture was quenched with 1N NaOH and then poured into a saturated aqueous NaHCO3. The precipitate which formed was collected and purified by preparative thin layer chromatography (16% MeOH/CH2CH2) to give the titled compound as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.25–1.40 (m, 2 H), 1.80–1.90 (m, 2 H), 2.50–2.90 (m, 5 H), 3.53 (brd, J=9.0 Hz, 2 H), 3.85–4.00 (m, 2 H), 4.00–4.10 (m, 1 H), 4.91 (brs, 1 H), 6.56 (d, J=5.7 Hz, 1 H), 6.61 (d, J=5.7 Hz, 1 H), 6.80–6.90 (m, 3 H), 6.96 (d, J=6.6 Hz, 2 H), 7.36 (dd, J=3.3, 1.2 Hz, 1 H), 7.41 (d, J=3.0 Hz, 1 H), 7.75 (d, J=3.0 Hz, 1 H), 7.88 (dd, J=6.0, 1.2 Hz, 1 H), 7.98 (d, J=6.0 Hz, 1 H), 8.54(d, J=3.3 Hz, 1 H), 10.60 (s, 1 H), 10.70 (s, 1 H); MS (ES) m/z: 621.0 (MH+); HRMS Calcd. for C30H33N6O5S2 (MH+): 621.1954. Found: 621.1952.
Reaction SMILES: C([O:3][P:4]([CH:9]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[P:10](=[O:17])([O:14]CC)[O:11]CC)(=[O:8])[O:5]CC)C.I[Si](C)(C)C.O.C(Cl)(Cl)Cl>C(Cl)Cl>[C:22]1([S:19]([NH:18][CH:9]([P:10](=[O:11])([OH:17])[OH:14])[P:4](=[O:3])([OH:8])[OH:5])(=[O:21])=[O:20])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOP(=O)(OCC)C(NS(=O)(=O)c1ccccc1)P(=O)(OCC)OCC
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=P(O)(O)C(NS(=O)(=O)c1ccccc1)P(=O)(O)O
Reaction time: 1.5 h
Yield: 64.9 %

Procedure:
To a solution of tetraethyl(phenylsulfonylaminomethylene)bis(phosphonate) (400 mg) in methylene chloride (4 ml), was added iodotrimethylsilane (0.8 ml) dropwise with stirring under nitrogen gas atmosphere in an ice-water bath. The mixture was stirred for 30 minutes at the same condition and then at ambient temperature for 1.5 hours. To the reaction mixture were added water (10 ml) and chloroform (8 ml) under ice-water bath cooling. The separated aqueous layer was washed with chloroform until its color disappeared and then evaporated in reduced pressure. The residue was washed with ethanol to give white powder of (phenylsulfonylaminomethylene)bis(phosphonic acid) (194 mg).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][OH:29])[CH2:12][CH:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:38][N:39]([CH3:44])[C:40](=[O:43])[CH:41]=[CH2:42].[H-].[Na+].C1OCCOCCOCCOCCOC1.[Cl-].[NH4+]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][O:29][CH2:42][CH2:41][C:40]([N:39]([CH3:44])[CH3:38])=[O:43])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=CC(=O)N(C)C
Reactant: CC(C)(C)[Si](C)(C)OC1CC2=CC[C@H]3[C@@H]4CC[C@H](CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CN(C)C(=O)CCOC[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 60.8 %

Procedure:
To 1α,3-bis(tert-butyldimethylsilyloxy)-17β-(hydroxymethyl)androst-5-ene (18.4 g), was added N,N-dimethylacrylamide (9.95 g), sodium hydride (60% in oil, 2.0 g), 15-crown-5 (2.2 g) and tetrahydrofuran (73.5 ml), followed by reaction at 0° C. for 8 hours. After stopping the reaction by adding a saturated aqueous ammonium chloride solution, the organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove the solvent. The resulting residue was mixed with methanol (90 ml), stirred at room temperature while under suspension, followed by centrifugation. The thus obtained solid was dried to give the titled compound (13.2 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:4][CH:3]=1.[F:14][C:15]([F:29])([F:28])[C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[CH2:24][CH2:23][N:22]([C:18]4[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:28])([F:29])[F:14])[CH:17]=4)[CH2:27][CH2:26]3)=[CH:3][CH:4]=2)[S:12][N:11]=1
Reactant: Cc1nsc(-c2ccc(F)cc2)n1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nsc(-c2ccc(N3CCN(c4cccc(C(F)(F)F)c4)CC3)cc2)n1
Temperature: 140 °C
Reaction time: 24 h
Yield: 51.5 %

Procedure:
A mixture of 5-(4-fluorophenyl)-3-methyl-1,2,4-thiadiazole (0.012 mol), 1-[3-(trifluoromethyl)phenyl]-piperazine (0.014 mol) and sodium carbonate (0.024 mol) in DMF (10 ml) was stirred at 140° C. for 24 hours, then at 150° C. for 24 hours, cooled, poured out into ice water (200 ml) and stirred. The precipitate was filtered off, taken up in DCM, dried, filtered and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 2.5g (52%) of 1-[4-(3-methyl-1,2,4-thiadiazol-5-yl)phenyl]-4-[3-(trifluoromethyl)phenyl]piperazine (compound 2).
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1>C(O)C>[NH2:7][CH2:6][CH:5]1[CH2:8][CH2:9][CH:2]([CH2:1][NH2:10])[CH2:3][CH2:4]1
Reactant: N#Cc1ccc(C#N)cc1
Solvent: CCO
Product: NCC1CCC(CN)CC1
Reaction time: 5 h
Yield: 8 %

Procedure:
Terephthalonitrile was hydrogenated following the procedure of Example 2 with ethanol as solvent but at a pressure of 500 psi. After 300 min. the reaction product was analyzed. It contained 8% yield of 1,4-bis(aminomethyl)cyclohexane and much byproduct showing that good results cannot be obtained at a pressure less than 750 psi.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17].[Cl:20][C:21]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:22]=1[NH2:23]>>[Cl:20][C:21]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:22]=1[NH:23][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: Cc1ccc(Cl)c(N)c1
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)OC)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)OC)cnc12
Yield: 100.3 %

Procedure:
In the same manner as in Example 1, step 4 and using methyl 7-chloro-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylate (2.2 g, 7.13 mmol) obtained in Example 21, step 2 and 2-chloro-5-methylaniline (1.64 g, 11.6 mmol), the title compound (2.78 g, 92%) was obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])[CH2:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=3)=O)=[CH:10][CH:9]=2)[CH2:5]1)(=[O:3])[CH3:2].Cl.[NH2:33][OH:34].C(=O)([O-])O.[Na+]>>[OH:34]/[N:33]=[C:16](/[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=1)\[CH2:15][C@H:14]([C:11]1[CH:10]=[CH:9][C:8]([CH:6]2[CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:7]2)=[CH:13][CH:12]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]
Reactant: NO
Reactant: CC(=O)N1CC(c2ccc([C@@H](CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)N1CC(c2ccc([C@@H](C/C(=N\O)c3ccnc(C)c3)c3ccccc3C)cc2)C1

Procedure:
In analogy to example 1, step 2, from (R)-3-(4-(1-acetylazetidin-3-yl)phenyl)-1-(2-methylpyridin-4-yl)-3-o-tolylpropan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a colourless oil, MS (ESI+): m/z=428.1 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[C@@H:3]([C:5]([O:7][CH3:8])=[O:6])[NH2:4].[C:11]([O-])(O)=[O:12].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:1][C:2]([CH3:10])([CH3:9])[C@@H:3]([C:5]([O:7][CH3:8])=[O:6])[N:4]=[C:11]=[O:12]
Reactant: O=C([O-])O
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H](N=C=O)C(C)(C)C

Procedure:
A solution (0.39 M) of methyl 3-methyl-L-valinate in a 2:1 mixture of saturated aqueous NaHCO3 and CH2Cl2 was cooled in an ice bath and stirred rapidly. The mixture was treated with triphosgene (0.45 eq) in one portion, and the resulting mixture was stirred for 0.5 h. The reaction was diluted with CH2Cl2, and the layers were separated. The aqueous phase was extracted with CH2Cl2, then the combined organics were washed with brine and dried. Removal of the solvent gave the title compound as clear oil that was kept for 12 h under vacuum (0.1 mbar) then used directly in the subsequent step. 1H NMR (400 MHz, CDCl3) δ 3.79 (s, 3H), 3.75 (s, 1H), 1.00 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[F:23])=[CH:8][C:3]=1[CH:4]=[N:5][NH:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.CC(OC)(C)C>C(Cl)Cl.O>[Br:12][C:10]1[CH:11]=[C:2]2[C:3]([CH:4]=[N:5][N:6]2[CH3:7])=[CH:8][C:9]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[F:23]
Reactant: CNN=Cc1cc(Oc2ccc([N+](=O)[O-])cc2F)c(Br)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc2cc(Oc3ccc([N+](=O)[O-])cc3F)c(Br)cc21
Temperature: 100 °C
Reaction time: 6 h
Yield: 80.7 %

Procedure:
1-(2,4-Dibromo-5-(2-fluoro-4-nitrophenoxy)benzylidene)-2-methylhydrazine (1.0 g, 2.2 mmol), cuprous chloride (22 mg, 0.2 mmol), potassium carbonate (0.638 g, 7.2 mmol), DMF (10 mL), and a stir bar are combined in a pressure tube under nitrogen. The cap is sealed and the tube is placed in an oil bath with stirring. The bath is heated to 100° C. over 30 min and held at 100° C. for 6 hours and then cooled to RT. The reaction mixture is poured into a separatory funnel containing MTBE (10 mL) and water (10 mL). The layers are separated and the aqueous layer is extracted with an additional portion of MTBE (10 mL). The organic layers are combined, and washed with water followed by saturated sodium chloride aqueous solution. The organic layer is dried over magnesium sulfate and concentrated to yield 0.70 g of crude product. The crude solid is dissolved in DCM and heptane, and then concentrated to remove DCM resulting in the formation of a slurry. The product is collected by filtration and dried under vacuum to give 6-bromo-5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazole as a solid (0.65 g, 79% yield). MS (m/z): 367.8 (M+H).
Reaction SMILES: [N:1]1[C:10]2[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].[BH4-].[Na+]>C(O)C.C(O)(=O)C>[N:1]1[C:10]2[CH:9]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=C1CCCc2cccnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCCNC1CCCc2cccnc21
Temperature: 150 °C

Procedure:
To a solution of 6,7-dihydroquinolin-8(5H)-one (2.0 g, 13.6 mmol) in ethanol (15 mL) was added concentrated acetic acid (5 drops), tert-butyl 4-aminobutylcarbamate (2.7 g, 14.3 mmol) and 4 Å molecular sieves. The reaction mixture was heated at 150° C. in microwave reactor for 10 min. The mixture was cooled to room temperature and NaBH4 (0.8 g, 20.4 mmol) was added all at once. The crude reaction mixture was absorbed onto silica gel and the product purified by silica gel chromatography (0% to 10% methanol/CH2Cl2) to afford the desired product: ESI+ MS: m/z (rel intensity) 320.2 (100, [M+H]+).
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([NH2:11])[CH:8]([CH3:10])[CH3:9].[BH4-].[Na+]>C(O)C>[CH:1]1([NH:11][CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)CN
Reactant: O=C1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)CNC1CCCC1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A mixture of cyclopentanone (10 g, 0.12 mol) and isobutyl amine (29.5 ml, 0.297 mol) was heated at 70° C. for 3 h under nitrogen. After cooling to 0° C., absolute ethanol (50 ml) was added to the reaction mixture, followed by sodium borohydride (6.59 g, 0.178 mol) in portions. The reaction mixture stirred at RT for 12 h, the solvent was removed under vacuum. The residue was taken up in MTBE and washed with water and brine. The organic layer was dried over Na2SO4, evaporated to dryness and the crude was purified by chromatography using silica gel (60-120 mesh), dichloromethane\methanol as eluent to afford of the titled compound as a yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([N+:13]([O-])=O)=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[Sn](Cl)Cl>Cl>[CH3:1][O:2][C:3]1[C:12]([NH2:13])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cccnc2c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Product: COc1ccc2cccnc2c1N
Yield: 70.6 %

Procedure:
In a similar fashion using route 1 general procedure 4, 7-methoxy-8-nitroquinoline (Intermediate 61) (250 mg, 1.22 mmol), tin (II) chloride (700 mg, 3.67 mmol) and 6N HCl (3 drops) gave the title compound (150 mg, 71%) which was used in the next step without purification.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:9]=[C:10]([C:17]([OH:19])=O)[C:11](=[CH:15][CH:16]=1)[C:12]([OH:14])=O.[NH2:21][CH2:22][C:23]([OH:25])=[O:24]>>[O:14]=[C:12]1[C:11]2[C:10](=[CH:9][C:8]([O:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:20])=[CH:16][CH:15]=2)[C:17](=[O:19])[N:21]1[CH2:22][C:23]([OH:25])=[O:24]
Reactant: NCC(=O)O
Reactant: Cc1ccccc1Oc1ccc(C(=O)O)c(C(=O)O)c1
Product: Cc1ccccc1Oc1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Temperature: 230 °C

Procedure:
A mixture of 4-(o-tolyloxy)phthalic acid (9.5 g, 35.0 mmol) and glycine (2.6 g, 35.0 mmol) was ground thoroughly in a mortar. The powder was then transferred to a flask and heated to 220-240° C. under high vacuum for 30 minutes. The reaction crude was cooled to room temperature to give the title compound in 10.2 g. 1H NMR (DMSO, 200 MHz): δ=7.89 (d, 1H, J=8.0 Hz), 7.42-7.08 (m, 6H), 4.27 (s, 2H), 2.14 (s, 3H).
Reaction SMILES: [Na].[O-]CC.[Br:5][C:6]1[C:7](=[O:15])[O:8][C:9](C)([CH3:13])[O:10][C:11]=1[CH3:12].Cl>C(O)C.CCOCC>[CH2:9]([O:8][C:7](=[O:15])[CH:6]([Br:5])[C:11]([CH3:12])=[O:10])[CH3:13]
Reactant: CC1=C(Br)C(=O)OC(C)(C)O1
Agent: CC[O-]
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(Br)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65729.7 %

Procedure:
Sodium metal (13.7 g, 0.59 mmol) was dissolved in 500 ml of absolute ethanol, and the resulting ethoxide solution was cooled to 0° C. Crude 5-bromo-2,2,6-trimethyl-4H-1,3-dioxin-4-one (115.5 g, 0.5 mmole at 95% purity) was then added, dropwise, to the chilled ethoxide solution over 30 minutes and the dark orange reaction mixture was stirred an additional 30 minutes at 0° C. The reaction was poured into 500 ml of ether and 550 ml of 1N HCl, and the organic layer was washed repeatedly with water (4×250 ml) and then dried over Na2SO4. Removal of solvent in vacuo (30° C., 2 Torr), followed by distillation on a 2-inch wiped-film molecular still (120° C. jacket, 0.2 Torr) afforded 68.7 g (71%) of a pale yellow oil (98% pure by gc).