Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.S(C)C.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][CH:28]=1.Cl>CO.ClCCl>[F:25][C:26]([F:36])([F:37])[C:27]1[CH:28]=[CH:29][C:30]([C@H:33]([OH:35])[CH3:34])=[CH:31][CH:32]=1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CSC
Product: C[C@@H](O)c1ccc(C(F)(F)F)cc1
Temperature: -45 °C
Reaction time: 0.17 h

Procedure:
To (S)-2-methyl-CBS-oxazaborolidine (Callery, 1M in toluene, 1 eq.) at −45° C. was added BH3.Me2S (1.06 eq.). This solution was stirred for 10 minutes at −45° C. and then placed in a −30° C. cooling bath before the slow dropwise addition of a 1M dichloromethane solution of 4′-(trifluoromethyl)acetophenone. The reaction mixture was allowed to stir for 214 3 hours at −30° C. After completion of the reaction, excess MeOH was added followed by 1N HCl. After warming up to room temperature, the resulting mixture was filtered through a pad of celite pad eluted with 30% EtOAc in hexane. The organic and aqueous layers were separated and the organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting oil was purified by flash chromatography (20% EtOAc in hexane) to afford the title compound.
Reaction SMILES: [C:1]1([N:7]2[CH:15]=[C:14]3[C:9]([N:10]=[C:11]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:12]=[C:13]3O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:25])=O.N>>[Cl:25][C:13]1[C:14]2[C:9](=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:15]=2)[N:10]=[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=1
Reactant: Oc1cc(-c2ccccc2)nc2nn(-c3ccccc3)cc12
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: Clc1cc(-c2ccccc2)nc2nn(-c3ccccc3)cc12
Reaction time: 1.5 h

Procedure:
5.5 g. of 2,6-diphenyl-2H-pyrazolo[3,4-b]pyridin-4-ol (0.019 mol.) and 27.5 ml. of phosphorus oxychloride are refluxed with stirring for 90 minutes. The colled mixture is poured onto crushed ice, then made alkaline with concentrated aqueous ammonia while adding ice. The collected 4-chloro-2,6-diphenyl-2H-pyrazolo[3,4-b]pyridine is washed with water and dried at 80°; m.p. 175°-177°. A sample, recrystallized from ethanol, melts at 176°-178°; yield: 5 g. (86%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:8])[CH2:4][CH2:3]1.[C:22]([Cl:30])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CCOCC>[ClH:30].[C:22]([O:8][C:5]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN1CCC(O)(c2ccccc2Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOCC
Product: CN1CCC(OC(=O)c2ccccc2)(c2ccccc2Cc2ccccc2)CC1
Product: Cl

Procedure:
2.0 g of 1-methyl-4-(α-phenyl-2-tolyl)-4-piperidinol, Example 1, is treated with 10 ml of benzoyl chloride with stirring and cooling. The reaction solution is diluted with 20 ml of ether, stirred for two hours and the resulting precipitate collected by suction filtration. The filter cake is washed well with ether and dried in vacuo at 40° C. over sodium hydroxide pellets. The dried filter cake is recrystallized twice from a chloroform-ether mixture to give colorless crystals, mp 197°-198° C. of 4-benzoyloxy-1-methyl-4-(α-phenyl-2-tolyl)piperidine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.[O:12]1CCOCC1>>[CH3:1][C:2]1[N:3]=[C:4]([CH:11]=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: C1COCCO1
Reactant: Cc1ccc([N+](=O)[O-])c(C)n1
Product: Cc1nc(C=O)ccc1[N+](=O)[O-]
Yield: 37.4 %

Procedure:
A solution of 2,6-dimethyl-3-nitropyridine (1.5 g, 9.85 mmol) and SeO2 (1.4 g, 12.81 mmol) in 1,4-dioxane (15 mL) was heated at reflux for 16 h. The reaction mixture was then filtered through Celite and the solvent was evaporated. The crude material obtained was purified by column chromatography (silica: 100-200 mesh, EtOAc:hexane 20-25%) to afford the title compound (0.61 g, 37.4%). δH (CDCl3) 10.09 (s, 1H), 8.39 (d, J=8.3 Hz, 1H), 7.97 (d, J=8.3 Hz, 1H), 2.94 (s, 3H).
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH:8]1C=CC=CC=1.CO.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[CH2:25][CH:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)[CH3:27]>CC(O)=O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[CH2:25][CH:26]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:8])=[O:33])=[CH:35][CH:36]=1)[CH3:27]
Reactant: COc1ccc(Br)c(CC(C)c2ccc(C(=O)O)cc2)c1
Reactant: c1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(C)Cc2cc(OC)ccc2Br)cc1

Procedure:
(Trimethylsilyl)diazomethane (2.0M hexanes, 4.8 mL) was added dropwise to a benzene/MeOH solution (7/3, 50 mL) containing the intermediate from Step A (2.8 g, 8.0 mmol). After 20 minutes AcOH was added dropwise to quench the excess reagent. The solution was concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.98 (d, J=8.2 Hz, 2H); 7.43 (d, J=8.2 Hz, 1H); 7.29 (d, J=8.2 Hz, 2H); 6.63 (dd, J=3.0, 8.7 Hz, 1H); 6.50 (d, J=3.0 Hz, 1H); 3.93 (s, 3H); 3.68 (s, 3H); 3.26-3.19 (m, 1H); 2.96 (d, J=7.0 Hz, 2H); 1.34 (d, J=6.9 Hz, 3H). LCMS1 4.14 min. (M-31)=331
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[NH2:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](=O)([O-:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[CH2:17][C@H:16]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[O-]
Reactant: N[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
200 mg of intermediate x (trans)-2-[4-(benzyloxy)phenyl]cyclopropanamine were dissolved in pyridine (5 mL) and tertbutyl carbonate (200 mg) was then added. The mixture was stirred at room temperature for 12 h, the poured into ice-water. The desired compound was filtered and dried. 1H-NMR (MeOH, 250 MHz, δ): 7.45-7.27 (m, 5H, ArH); 6.96 (d, 8.5 Hz, 2H, ArH); 6.86 (d, J=8.5 Hz, 2H, ArH); 5.03 (s, 2H, CH2); 2.41-2.34 (m, 1H, CH); 1.86-1.76 (m, 10H, CH); 0.98-0.85 (m, 2H, CH2).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)[CH:11]=[C:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH:30]1[C:42]2[C:41]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[NH:35][C:34]=2[CH:33]=[CH:32][N:31]=1.C(=O)([O-])[O-].[K+].[K+].CCCCCCCCCCCC>[Cu].C(Cl)(Cl)Cl.CS(C)=O>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[C:12]1[CH:11]=[C:10]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([N:35]3[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:41]=4[C:42]4[CH:30]=[N:31][CH:32]=[CH:33][C:34]3=4)[N:7]=2)[CH:13]=1
Reactant: c1ccc2c(c1)[nH]c1ccncc12
Reactant: Brc1cccc(-c2cc(-c3ccc4ccccc4c3)cc(-c3ccccn3)n2)n1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Solvent: CCCCCCCCCCCC
Product: c1ccc(-c2cc(-c3ccc4ccccc4c3)cc(-c3cccc(-n4c5ccccc5c5cnccc54)n3)n2)nc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To 4.2 g of the resulting 6-bromo-4′-(naphthalen-2-yl)-[2,2′;6′,2″]terpyridine were added 1.6 g of 5H-pyrido[4,3-b]indole, 0.3 g of a copper powder, 4.0 g of potassium carbonate, 0.3 mL of dimethyl sulfoxide, and 10 mL of n-dodecane, followed by heating and stirring at 150° C. for 8 hours. After cooling to room temperature, 80 mL of chloroform was added thereto to remove an insoluble matter by filtration, and the filtrate was concentrated under a reduced pressure to obtain a crude product. The crude product was purified by column chromatography (carrier: NH silica gel, eluent: hexane/chloroform) to obtain 2.2 g (yield, 43%) of 4′-(naphthalen-2-yl)-6-(5H-pyrido[4,3-b]indol-5-yl)-[2,2′;6′,2″]terpyridine (Compound 27) as a white powder.
Reaction SMILES: [Si]([C:8]1[O:9][C:10]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:11]=2[C:12]=1[C:13](=[O:26])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:25][O:24][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([O:20][CH3:21])[C:17]=1[O:22][CH3:23])[C:13]([C:12]1[C:11]2[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:10]=2[O:9][CH:8]=1)=[O:26]
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c([Si](C)(C)C(C)(C)C)oc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)coc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.4 %

Procedure:
To a stirred solution of 2-t-butyldimethylsilyl-3-(3,4,5-trimethoxy-benzoyl)-6-methoxy-benzofuran (30 mg, 0.066 mmol) in tetrahydrofuran (1 mL) was added tetrabutylammoniumfluoride (76.5 μL, 0.076 mmol, 1M solution in tetrahydrofuran). The reaction mixture was stirred at room temperature for 20 minutes (monitored by tlc), diluted with ethyl acetate (10 mL) and washed with 1M hydrochloric acid (5 mL). The organic layer was dried over magnesium sulfate and the solvent was removed under vacuum. The crude product was purified by flash chromatography (silica gel, eluent=hexane/diethyl ether; 7:3) to afford the title product as a cream crystalline solid (19.3 mg, 86%); 1H NMR (300 MHz, CDCl3) δ 8.02(d, 1H, J=8.97 Hz), 8.01(s, 1H, C2H), 7.14(s, 2H, benzoyl Hs), 7.05(d, 1H, J=2.11 Hz), 7.00(dd, 1H, J=8.63, 2.11 Hz), 3.93(s, 3H, OMe), 3.90(s, 6H, 2×OMe), 3.87(s, 3H, OMe); 13C NMR (75 MHz, CDCl3) δ 188.71(CO), 158.64, 156.31, 152.82, 150.22, 141.72, 133.97, 122.58, 120.87, 118.12, 113.11, 106.07, 95.53, 60.63, 55.99, 55.40.
Reaction SMILES: CN(C=O)C.[CH3:6][C:7]1[C:8]2[CH:29]=[CH:28][CH:27]=[CH:26][C:9]=2[S:10][C:11]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C([O-])([O-])=O.[K+].[K+].[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][C:38]=1[C:45]([F:48])([F:47])[F:46]>CCOC(C)=O.O>[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][N:12]([C:11]2[S:10][C:9]3[CH:26]=[CH:27][CH:28]=[CH:29][C:8]=3[C:7]=2[CH3:6])[S:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:21]=2)(=[O:15])=[O:14])=[CH:39][C:38]=1[C:45]([F:46])([F:47])[F:48]
Reactant: Fc1ccc(CBr)cc1C(F)(F)F
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2sc3ccccc3c2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(F)c(C(F)(F)F)c2)c2sc3ccccc3c2C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 12-L 4-neck flask equipped with an overhead mechanical stirrer, N2 inlet/outlet adapter, and thermocouple was charged with DMF (4.9 L), N-(3-methylbenzo[b]thiophen-2-yl)-4-carbomethoxy-benzenesulfonamide (245 g, 0.68 mol) and K2CO3 (112 g, 0.81 mol). 4-Fluoro-3-(trifluoromethyl)benzyl bromide (210 mL, 0.81 mol) was then added drop-wise over 15 min and the resulting mixture was stirred for 18 h at room temperature. The resulting mixture was poured into cold H2O (10 L), stirred for 30 min, to which was then added EtOAc (4 L). The layers were separated and the aqueous phase was extracted with EtOAc (2×1 L). The combined EtOAc layers were washed with brine (1 L), dried over Na2SO4, filtered and evaporated under reduced pressure to yield a residue. The residue was purified using flash column chromatography (SiO2) eluting with heptane-EtOAc to yield N-[4-fluoro-3-(trifluoromethyl)-benzyl]-N-(3-methylbenzo[b]thiophen-2-yl)-4-carbomethoxy-benzenesulfonamide as a white solid. 1H-NMR (DMSO-d6) δ 8.21 (d, 2H), 8.03 (d, 2H), 7.86-7.83 (m, 1H), 7.71-7.63 (m, 3H), 7.45-7.37 (m, 3H), 4.89 (br s, 2H), 3.93 (s, 3H), 1.94 (s, 3H).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C@@H:5]1[NH:29][C:27](=[O:28])[C@@H:26]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH3:39])=[CH:35][CH:36]=2)[NH:25][C:23](=[O:24])[CH2:22][CH2:21][S:20][S:19][CH2:18][C@@H:17]([C:40]([N:42]2[C@H:46]([C:47]([NH:49][C@H:50]([C:55]([NH:57][CH2:58][C:59]([NH2:61])=[O:60])=[O:56])[CH2:51][CH2:52][CH2:53][NH2:54])=[O:48])[CH2:45][CH2:44][CH2:43]2)=[O:41])[NH:16][C:14](=[O:15])[C@H:13]([CH2:62][C:63]([NH2:65])=[O:64])[NH:12][C:10](=[O:11])[C@H:9]([C@H:66]([OH:68])[CH3:67])[NH:8][C:6]1=[O:7])[CH3:4].O.N.OO>C(#N)C>[CH3:1][CH2:2][C@@H:3]([C@@H:5]1[NH:29][C:27](=[O:28])[C@@H:26]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH3:39])=[CH:35][CH:36]=2)[NH:25][C:23](=[O:24])[CH2:22][CH2:21][S:20][S:19][CH2:18][C@@H:17]([C:40]([N:42]2[C@H:46]([C:47]([NH:49][C@H:50]([C:55]([NH:57][CH2:58][C:59]([NH2:61])=[O:60])=[O:56])[CH2:51][CH2:52][CH2:53][NH2:54])=[O:48])[CH2:45][CH2:44][CH2:43]2)=[O:41])[NH:16][C:14](=[O:15])[C@H:13]([CH2:62][C:63]([NH2:65])=[O:64])[NH:12][C:10](=[O:11])[CH:9]([C@H:66]([OH:68])[CH3:67])[NH:8][C:6]1=[O:7])[CH3:4]
Reactant: CCOc1ccc(C[C@H]2NC(=O)CCSSC[C@@H](C(=O)N3CCC[C@H]3C(=O)N[C@@H](CCCN)C(=O)NCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H]([C@@H](C)CC)NC2=O)cc1
Agent: N
Agent: OO
Solvent: O
Solvent: CC#N
Product: CCOc1ccc(C[C@H]2NC(=O)CCSSC[C@@H](C(=O)N3CCC[C@H]3C(=O)N[C@@H](CCCN)C(=O)NCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)C([C@@H](C)O)NC(=O)[C@H]([C@@H](C)CC)NC2=O)cc1
Reaction time: 1 h

Procedure:
2.95 g of atosiban acetate is prepared by dissolving the linear atosiban obtained from Example 2 in 250 ml of 10% acetonitrile aqueous solution, adjusting the pH value to 8 to 9 with 30% ammonia water, adding 0.85 g of H2O2, reacting for 60 min at 25° C., monitoring with HPLC (HPLC: 83.5%), filtering after reaction, purifying filtrate by preparative RP-HPLC (column C18 or C8), transferring salt, and freeze-drying, MS: 994.5, HPLC: 99.4%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:25])[O:10][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[CH:12]=2)=[CH:4][C:3]=1[CH3:26].[Li]CCCC.[C:32](=[O:34])=[O:33].Cl>C1COCC1.CCCCCC.CCOCC>[Cl:24][C:19]1[CH:18]=[C:17]([C:11]2([C:13]([F:16])([F:15])[F:14])[O:10][N:9]([CH3:25])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:32]([OH:34])=[O:33])=[C:3]([CH3:26])[CH:4]=3)=[CH:12]2)[CH:22]=[C:21]([Cl:23])[CH:20]=1
Reactant: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1Br
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1C(=O)O
Temperature: -90 °C
Reaction time: 1 h

Procedure:
210 mg of 3-(4-Bromo-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazole (IIIa) was dissolved in 20 ml of dry THF, cooled to −90° C. and treated with 0.625 ml BuLi 1.6M in hexane. The mixture was stirred for 1 hour at −80° C. and then a great excess of solid CO2 was added to the mixture. The temperature was allowed to rise up to −30° C. (1 hour) and 5 ml of 1M HCl was added followed with ether. The organic layer was dried and evaporated to dryness. The residual resin was used in the final step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11](C(O)=O)=[N:10]2)=[CH:5][CH:4]=1.C([N:23](CC)CC)C.Cl[C:29]([O:31][CH2:32]C(C)C)=[O:30].[N-]=[N+]=[N-].[Na+]>CC(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]([NH:23][C:29]([O:31][CH3:32])=[O:30])=[N:10]2)=[CH:7][CH:8]=1
Reactant: CC(C)COC(=O)Cl
Reactant: COC(=O)c1cc(C(=O)O)nn1-c1ccc(OC)cc1
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)Nc1cc(C(=O)OC)n(-c2ccc(OC)cc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-5-(methoxycarbonyl)pyrazole-3-carboxylic acid (3.0 g, 10.9 mmol) in 50 mL of acetone at 0° C. was added triethylamine (1.66 mL, 11.9 mmol) followed by iso-butyl chloroformate (1.14 mL, 11.9 mmol). The resulting was stirred for 30 min whereupon an aqueous solution of sodium azide (2.82 g, 43.4 mmol) was added. The reaction was stirred at 0° C. for 1 h. The reaction was then diluted with ethyl acetate and washed with brine. The organics were dried (MgSO4) and concentrated in vacuo. The residue was dissolved in 50 mL of toluene and stirred at 100° C. for 1 h. The volatiles were removed in vacuo and the residue was dissolved in methanolic sodium methoxide (5 mL of a 25% solution of sodium methoxide in methanol, 21 mmol) and stirred at ambient temperature for 2 h. The reaction was diluted with ethyl acetate, washed with wtaer and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (elution with 1:1 hexanes/ethyl acetate) to afford 1.1 g (33%) of the title compound as a solid. LRMS (DCI): 306.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][CH2:13][Cl:14])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)[NH2:19]>C(O)(C)C>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][CH2:13][Cl:14])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: ClCCCn1ccc2ncnc(Cl)c21
Solvent: CC(C)O
Product: Fc1cccc(COc2ccc(Nc3ncnc4ccn(CCCCl)c34)cc2Cl)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 73.3 %

Procedure:
A mixture of 4-chloro-5-(3-chloropropyl)-5H-pyrrolo[3,2-d]pyrimidine (839 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (1.10 g) and isopropyl alcohol (5 mL) was stirred at 80° C. for 1.5 hrs. The mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=90:10→20:80) to give the title compound (1.19 g).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:22]3[N:21]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:28]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2ncccn2)c1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2ncccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 3-(pyrimidin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 418.38 g/mol.
Reaction SMILES: C([Al])C.[CH:4]([OH:7])([CH3:6])[CH3:5].[C-:8]#[N:9].[CH2:10]([Al+:12][CH2:13][CH3:14])[CH3:11]>C1COCC1>[Al:12]([C:8]#[N:9])([CH2:13][CH3:14])[CH2:10][CH3:11].[CH3:5][CH:4]([OH:7])[CH3:6]
Reactant: [C-]#N
Reactant: CC[Al+]CC
Agent: CC[Al]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC[Al](C#N)CC

Procedure:
The sulfinimine-mediated asymmetric synthesis involves addition of ethylaluminium cyanoisopropoxide generated in situ by addition of isopropanol (i-PrOH) to diethylaluminium cyanide (Et2AlCN) to the compound VIIa. Thus treatment of compound VIIa (1.0 mmol) at −78° C. in THF with 1.5/1.0 equiv of Et2AlCN/i-PrOH gave amino nitrile VIII in good yield (50-70%).
Reaction SMILES: [C:1](=[O:17])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C:3]1([CH3:6])[CH2:5][CH2:4]1.[CH3:18][S:19]([N:22]1[CH2:27][CH:26]=[C:25]([C:28]2[CH:29]=[C:30]3[CH2:44][C:35]4([CH2:43][C:37]5([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]5)[CH2:36]4)[O:34][C:31]3=[CH:32][N:33]=2)[CH2:24][CH2:23]1)(=[O:21])=[O:20].C(N(CC)CC)C.O1CCCC1>O>[CH3:18][S:19]([N:22]1[CH2:23][CH:24]=[C:25]([C:28]2[CH:29]=[C:30]3[CH2:44][C:35]4([CH2:36][C:37]5([CH2:38][CH2:39][N:40]([C:1]([O:2][C:3]6([CH3:6])[CH2:4][CH2:5]6)=[O:17])[CH2:41][CH2:42]5)[CH2:43]4)[O:34][C:31]3=[CH:32][N:33]=2)[CH2:26][CH2:27]1)(=[O:21])=[O:20]
Reactant: CC1(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(OC(=O)N2CCC3(CC2)CC2(Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O2)C3)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1-Methylcyclopropyl 4-nitro-phenyl carbonate (58 mg) is added to a mixture of 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt; 66 mg), triethylamine (65 μL), and tetrahydrofuran (5 mL) at room temperature. The solution is stirred at 60° C. overnight. Water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 4:1→1:4) to give the title compound. LC (method 1): tR=1.02 min; Mass spectrum (ESI+): m/z=488 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[C:10]=2[CH3:12])S[CH2:4][CH2:3]1.OO.[S:20]([O-:23])(O)=[O:21].[Na+]>C(O)(=O)C>[CH3:17][C:2]1([CH3:1])[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[C:10]=2[CH3:12])[S:20](=[O:23])(=[O:21])[CH2:4][CH2:3]1
Reactant: Cc1cc(C(=O)O)c(C)c2c1SCCC2(C)C
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC2(C)C
Temperature: 80 °C
Yield: 90 %

Procedure:
4 ml of acetic acid was added to 5 g (0.02 mol) of 4,4,5,8-tetramethylthiochroman-6-carboxylic acid, further, 6.9 g (0.06 mol) of a 30% hydrogen peroxide aqueous solution was added, and the mixture was heated at 80° C. for 2 hours. 50 ml of a 2% sodium hydrogensulfite aqueous solution was added to the reaction mixture, and a precipitated solid was recovered by filtration to give 5.1 g (yield 90%) of 4,4,5,8-tetramethylthiochroman-6-carboxylic acid-1,1-dioxide.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N)(=O)C1C=CC=CC=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=1[C:23]([NH:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[CH:29][NH:30]2)=[O:24]>CCOCC>[CH3:2][C:1]([NH:5][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=1[C:23]([NH:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[CH:29][NH:30]2)=[O:24])([CH3:4])[CH3:3]
Reactant: CC(C)(C)N
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCCCCBr
Agent: NC(=O)c1ccccc1
Solvent: CCOCC
Product: CC(C)(C)NCCCCOc1ccccc1C(=O)Nc1cccc2[nH]ccc12

Procedure:
Using the procedure of Example 30 but at 50° C. and replacing tert-pentylamine by tert-butylamine and 2-(3-chloropropoxy)-N-1H-indol-4-yl)benzamide by 2-(4-bromobutoxy)-N-(1H-indol4-yl)benzamide, and with chromatography on silica (eluant:CHCl3 /acetone/TEA of 6:3:1), the residue was taken up in ether to obtain 2-[4-[1,1-dimethylethylamino)-butoxy]-N-(1H-indol-4-yl)benzamide melting at 147° C. The acid fumarate which melted at 224°-225° C. with sublimation after crystallization from ethanol, was prepared.