Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=2.CO.[CH2:22](P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH3:22][O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=2
Reactant: CC(C)(C)OC(=O)Cc1ccc2ncc(O)cc2c1
Reactant: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Solvent: CO
Product: COc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of tert-butyl 2-(3-hydroxyquinolin-6-yl)acetate (0.1 g, 0.4 mmol) in benzene (5 mL) was added methanol (0.05 ml, 1 mmol) and tributylphosphine (0.1 ml, 0.6 mmol). The resulting mixture was cooled to 0° C. followed by adding 1.1′-(azodicarbonyl)dipiperidine (0.1 g, 0.6 mmol). After 10 min, ice bath was removed; the reaction mixture was warmed up to rt. The reaction mixture was continued to stir for 20 h. TLC showed about 80% conversion. More MeOH (1 ml), tibutylphosphine (0.05 mL), and ADDP (50 mg) were added and allowed to stir for 3 h. Hexane was added to the reaction mixture and dihydro-ADDP separated out and was filtered off. The filtrate was concentrated. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-027, 40 g SiO2) to afford the desired product as colorless liquid. MS m/z: 274.3 (M+H). Calc'd. for C16H19NO3—273.2.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][C:10]([C:12]1[CH:22]=[CH:21][C:15]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:14][CH:13]=1)=[O:11])C1C=CC=CC=1.O.Cl.[H][H]>[Pd].CO>[NH2:8][CH2:9][CH:10]([C:12]1[CH:22]=[CH:21][C:15]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:14][CH:13]=1)[OH:11]
Reactant: [H][H]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(C(O)CN)cc1

Procedure:
4'-(2-Dibenzylaminoacetyl)methanesulfonanilide (XXVI) (32.7 g) and Pd/C catalyst (1.5 g) were combined in MeOH (200 ml), H2O (25 ml), and concentrated HCl (6.6 ml) and shaken for 24 hours at 35° C. and 3 atmospheres pressure of hydrogen gas in a Parr hydrogenator, by which time three equivalents of hydrogen had been consumed. The catalyst was filtered off and the filtrate was evaporated to a white solid, which was recrystallized twice from 2-PrOH/H2O. This yielded 4.3 g of Compound (XXV).HCl, m.p. 178°-180°, whose elemental analysis for C, H, and N, NMR, and mass spectra were consistent with the indicated structure.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([NH:15][C:16]3[C:21]([CH3:22])=[CH:20][C:19]([C:23]([F:35])([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[C:24]([F:27])([F:26])[F:25])=[CH:18][C:17]=3[CH2:36][CH3:37])=[O:14])[CH:9]=2)[N:4]=1)#[N:2].NC(N)=[O:40].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([NH:15][C:16]3[C:21]([CH3:22])=[CH:20][C:19]([C:23]([F:35])([C:28]([F:34])([F:33])[C:29]([F:30])([F:31])[F:32])[C:24]([F:25])([F:26])[F:27])=[CH:18][C:17]=3[CH2:36][CH3:37])=[O:14])[CH:9]=2)[N+:4]=1[O-:40])#[N:2]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2nc(C#N)ccc2c1
Reactant: NC(N)=O
Agent: OO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2c(ccc(C#N)[n+]2[O-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.9 %

Procedure:
2-Cyano-N-[2-ethyl-6-methyl-4-(1,1,1,2,3,3,4,4,4-nonafluorobutan-2-yl)phenyl]quinoline-6-carboxamide (240 mg) was dissolved in dichloromethane, added with urea-hydrogen peroxide adduct (85 mg) and trifluoroacetic anhydride (190 mg), and stirred at room temperature for 20 hours. The reaction solution was concentrated under the reduced pressure, and the resulting residues were dissolved in ethyl acetate. The solution was washed with water and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was removed by distillation under the reduced pressure. The resulting residues were purified by column chromatography to obtain 2-cyano-N-[2-ethyl-6-methyl-4-(1,1,1,2,3,3,4,4,4-nonafluorobutan-2-yl)phenyl]quinoline-6-carboxamide-1-oxide (0.20 g, 81%).
Reaction SMILES: [CH2:1]([CH:5](C(O)=O)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=1[CH3:21].N1CCCCC1.Cl>N1C=CC=CC=1>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([OH:8])=[O:7])=[CH:15][C:14]=1[CH3:21]
Reactant: Cc1cc(C=O)ccc1F
Reactant: CCCCC(C(=O)O)C(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCCCC(=Cc1ccc(F)c(C)c1)C(=O)O
Temperature: 100 °C
Reaction time: 16 h
Yield: 80.1 %

Procedure:
A mixture of 2-butyl-malonic acid (2.319 g, 14.482 mmol), 4-fluoro-3-methylbenzaldehyde (1.000 g, 7.241 mmol), and piperidine (1.232 g, 14.482 mmol) in 10 mL of pyridine was heated to 100° C. and stirred at this temperature for 16 h. After cooling to room temperature, the reaction mixture was poured into 25 mL of concentrated HCl containing 50 g of ice, and then extracted with ethyl acetate. The organic extracts were combined and dried over anhydrous Na2SO4, concentrated under reduced pressure, the product isolated by Flash chromatography (silica gel) eluting with 0-30% ethyl acetate/hexanes to give the title compound as yellow liquid (1.370 g, 80% yield). LC-MS: tR=9.5 min; m/z 237 (M+H)+.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3CCN)[CH2:16][CH2:15][CH2:14][C:13]=2[CH:30]=1)(C(C)(C)C)(C)C.Cl.[N:32]1([CH2:39][CH2:40][O:41][C:42]2[CH:50]=[CH:49][C:45]([C:46](O)=O)=[CH:44][CH:43]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.[N:51]1(CCOC2C=CC(CNCCC3C=C(OC)C=CC=3C3CCCC4C=C(O[Si](C(C)(C)C)(C)C)C=CC=4C3)=CC=2)CCCC[CH2:53][CH2:52]1>>[N:32]1([CH2:39][CH2:40][O:41][C:42]2[CH:50]=[CH:49][C:45]([CH2:46][CH2:53][CH2:52][NH:51][C:20]3[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=3[CH:17]3[CH2:16][CH2:15][CH2:14][C:13]4[CH:30]=[C:9]([OH:8])[CH:10]=[CH:11][C:12]=4[CH2:18]3)=[CH:44][CH:43]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Reactant: COc1ccc(C2CCCc3cc(O[Si](C)(C)C(C)(C)C)ccc3C2)c(CCNCc2ccc(OCCN3CCCCCC3)cc2)c1
Reactant: COc1ccc(C2CCCc3cc(O[Si](C)(C)C(C)(C)C)ccc3C2)c(CCN)c1
Agent: Cl
Product: COc1ccc(C2CCCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CCCCCC3)cc2)c1

Procedure:
Synthesized from {2-[2-(tert-butyldimethylsilyloxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-5-methoxyphenyl}ethylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl]{2-[2-(tert-butyldimethyl silyloxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-5-methoxyphenyl}ethylamine (584 mg) was used according to an analogous synthetic method to Example 325 described below to provide the title compound (426 mg).
Reaction SMILES: OC(C(F)(F)F)=O.[CH2:8]1[C:11]2([CH2:15][CH2:14][CH2:13][NH:12]2)[CH2:10][O:9]1.[F:16][CH:17]([F:46])[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][C:27]([C:29]([N:31]3[CH2:34][CH:33]([O:35][C:36]4[CH:43]=[CH:42][C:39]([CH:40]=O)=[C:38]([O:44][CH3:45])[CH:37]=4)[CH2:32]3)=[O:30])=[N:26][N:25]=2)=[CH:20][CH:19]=1.C(N(CC)CC)C.[Na]>ClCCl>[CH2:10]1[C:11]2([CH2:15][CH2:14][CH2:13][N:12]2[CH2:40][C:39]2[CH:42]=[CH:43][C:36]([O:35][CH:33]3[CH2:34][N:31]([C:29]([C:27]4[O:28][C:24]([C:21]5[CH:20]=[CH:19][C:18]([CH:17]([F:46])[F:16])=[CH:23][CH:22]=5)=[N:25][N:26]=4)=[O:30])[CH2:32]3)=[CH:37][C:38]=2[O:44][CH3:45])[CH2:8][O:9]1
Reactant: COc1cc(OC2CN(C(=O)c3nnc(-c4ccc(C(F)F)cc4)o3)C2)ccc1C=O
Reactant: C1CNC2(C1)COC2
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC2CN(C(=O)c3nnc(-c4ccc(C(F)F)cc4)o3)C2)ccc1CN1CCCC12COC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
2-Oxa-5-azaspiro[3.4]octane TFA salt (0.11 g, ca. 70%, 0.34 mmol) and 4-(1-(5-(4-(difluoromethyl)phenyl)-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)-2-methoxybenzaldehyde (0.146 g, 0.34 mmol) were mixed in dichloromethane (2 ml). Triethylamine (0.1 ml, 0.72 mmol) was added, followed by sodium triacetoxyhydroborate (0.145 g, 0.68 mmol). The mixture was stirred at ambient temperature overnight. An LC-MS showed complete consumption of starting materials. The reaction mixture was then diluted with dichloromethane (10 ml) and shaken with NaHCO3 (sat. 3 ml). The two phases were separated by the use of a phase separator. Evaporation of the organic phase afforded a residue, which was purified by preparative reverse-phase HPLC at pH 10 to give 0.119 g (67%) of the desired product as a solid. 1H NMR (500 MHz, CDCl3): δ 1H NMR (600 MHz, DMSO) δ 1.56-1.68 (m, 2H), 2.06-2.14 (m, 2H), 2.55-2.58 (m, 2H), 3.81 (s, 3H), 3.88 (s, 2H), 4.11 (dd, 1H), 4.44 (d, 2H), 4.54-4.59 (m, 1H), 4.63-4.68 (m, 1H), 4.79 (d, 2H), 5.09-5.13 (m, 1H), 5.17-5.22 (m, 1H), 6.42 (dd, 1H), 6.54 (d, 1H), 7.18 (t, 1H), 7.21 (d, 1H), 7.85 (d, 2H), 8.23 (d, 2H). MS (APCI+) m/z 527.2 [M+H]+, LC purity: 97%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[CH2:18]([S:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([F:29])[CH:28]=1)[NH2:25])[CH3:19]>>[CH2:18]([S:20][CH2:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=3[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=2)[CH:26]=[C:27]([F:29])[CH:28]=1)[CH3:19]
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Reactant: CCSCc1cc(N)cc(F)c1
Product: CCSCc1cc(F)cc(Nc2ncc(F)c(-c3ccc(F)cc3OC)n2)c1

Procedure:
Intermediate 42.3 was prepared under similar conditions as described in the preparation of Intermediate 20.1 using 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine and 3-[(ethylsulfanyl)methyl]-5-fluoroaniline. The batch was purified by chromatography (hexane to hexane/ethyl acetate 30%) to give the desired product.
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]=[C:14]=[O:15])[C:10]([F:16])=[CH:9][C:8]=1[Cl:17])(=[O:5])=[O:4].[F:18][C@@H:19]1[CH2:23][NH:22][C@@H:21]([C:24]([OH:26])=[O:25])[CH2:20]1>O1CCCC1>[Cl:17][C:8]1[C:7]([NH:6][S:3]([CH2:2][Cl:1])(=[O:4])=[O:5])=[CH:12][C:11]([NH:13][C:14]([N:22]2[CH2:23][C@@H:19]([F:18])[CH2:20][C@@H:21]2[C:24]([OH:26])=[O:25])=[O:15])=[C:10]([F:16])[CH:9]=1
Reactant: O=C(O)[C@H]1C[C@H](F)CN1
Reactant: O=C=Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Solvent: C1CCOC1
Product: O=C(O)[C@H]1C[C@H](F)CN1C(=O)Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
1-chloro-N-(2-chloro-4-fluoro-5-isocyanatophenyl)methanesulfonamide (120 g, 401 mmol) was dissolved in 400 mL of dry tetrahydrofuran. 55.8 g (420 mmol) of (2R-trans)-4-fluoro-2-pyrrolidinecarboxylic acid was added in a single portion and the mixture was stirred overnight at room temperature. The mixture was then filtered and the tetrahydrofuran was evaporated under reduced pressure. The residue was dissolved in 800 mL of ethyl acetate, a solution of 86.0 g of sodium bicarbonate in 870 mL of water was added and then solid sodium chloride was added to saturate the aqueous layer. The aqueous layer was separated, washed with 250 mL of ethyl acetate, and then with diethyl ether (twice with 250 mL). The aqueous layer was then added slowly to a stirred mixture of 120 mL of concentrated hydrochloric acid, 240 mL of water, and 800 mL of tetrahydrofuran. Solid sodium chloride was then added to saturate the aqueous layer, the layers were separated, and the aqueous layer was extracted with 100 mL of tetrahydrofuran. The tetrahydrofuran layers were combined, dried over magnesium sulfate, and evaporated under reduced pressure to afford 173.43 g of the title compound as a glassy solid, suitable for use in the next step. 1H NMR (DMSO-d6): δ 2.0-2.3 (m, 1H), 2.5-2.6 (m, 1H), 3.66 (m, 1H), 3.86 (m, 1H), 4.97 (s, 2H), 5.40 (d, J=54 Hz, 1H), 7.52 (d, 1H), 7.66 (d, 1H), 8.48 (s, 1H), 10.10 (br s, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH2:29][CH2:30][C:31]=4[N:32]=3)=[O:23])[CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.C(N(CC)CC)C.Br[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].C(OCC)(=O)C>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH:29]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:30][C:31]=4[N:32]=3)=[O:23])[CH2:20][CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(c1nc2c(s1)CNCC2)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)sc2CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In N,N-dimethylformamide (50 ml) was dissolved 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride (240 mg), followed by the addition of triethylamine (0.28 ml) and then tert-butyl bromoacetate (0.14 ml). The resulting mixture was stirred overnight at room temperature. After concentration of the reaction mixture under reduced pressure, ethyl acetate was added to the residue. The resulting mixture was washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (Φ3.0×12.0 cm, hexane:ethyl acetate 3:2), whereby the title compound (207 mg) was obtained as a colorless foam.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH2:14][N:12]2[CH2:13][C@@H:5]([CH2:6][C@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:27]=[C:26]4[C@@:28]56[C@@H:39]([N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:53][CH3:54])[C@@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@H:37]([O:47][C:48]([CH3:50])=[O:49])[C@:33]3([CH2:51][CH3:52])[CH:34]=[CH:35][CH2:36][N:31]([C@H:32]53)[CH2:30][CH2:29]6)[C:8]3[NH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:9]=3[CH2:10][CH2:11]2)[CH:4]=1.[Na].[O:60]1CCCC1>>[CH3:1][CH2:2][C@@:3]12[O:60][C@@H:4]1[C@H:5]1[CH2:13][N:12]([CH2:11][CH2:10][C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[NH:21][C:8]=3[C@@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:27]=[C:26]4[C@:28]56[C@@H:32]7[C@:33]([CH2:51][CH3:52])([C@@H:37]([O:47][C:48]([CH3:50])=[O:49])[C@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@@H:39]5[N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:53][CH3:54])[CH:34]=[CH:35][CH2:36][N:31]7[CH2:30][CH2:29]6)[CH2:6]1)[CH2:14]2
Reactant: CCC1=C[C@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Reactant: C1CCOC1
Agent: [Na]
Product: CC[C@]12CN3CCc4c([nH]c5ccccc45)[C@@](C(=O)OC)(c4cc5c(cc4OC)N(C)[C@H]4[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]6(CC)C=CCN7CC[C@]54[C@@H]76)C[C@H](C3)[C@H]1O2

Procedure:
To a solution of 50 mg. of 3',4'-anhydro-vinblastine in 5 ml. of tetrahydrofuran 50 mg. of a 15% aqueous sodium hychlorite solution is added.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][N:7]=1.[C@@H:8]1([NH2:17])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1>CO>[NH3:7].[C@@H:8]1([NH:17][C:3]2[CH2:4][CH2:5][CH2:6][N:7]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: COC1=NCCC1
Reactant: N[C@H]1C=Cc2ccccc21
Solvent: CO
Product: N
Product: c1ccc2c(c1)CC[C@@H]2NC1=NCCC1
Temperature: 25 °C
Reaction time: 40 h
Yield: 5 %

Procedure:
To a solution of 5-methoxy-3,4-dihydro-2H-pyrrole (520 mg) in MeOH (8 mL) was added (1S)-1H-inden-1-amine, 2,3-dihydro (538 mg, 4.04 mmol, CAS 61341-86-4) at room temperature. The mixture was stirred at room temperature for 40 h. The reaction was then cooled to room temperature and concentrated. Flash column chromatography (5% 7N NH3 in MeOH/DCM) yielded (S)—N-(2,3-dihydro-1H-inden-1-yl)-3,4-dihydro-2H-pyrrol-5-amine, as a white solid. 1H NMR (300 MHz, CDCl3) δ: 7.30-7.39 (m, 5H), 7.13-7.28 (m, 3H), 5.25-5.38 (m, 1H), 3.72 (t, J=6.7 Hz, 2H), 2.91-3.04 (m, 1H), 2.77-2.91 (m, 1H), 2.54-2.72 (m, 1H), 2.35-2.54 (m, 2H), 1.93-2.10 (m, 2H), 1.76-1.91 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH3:7][O:8][CH2:9][CH2:10][Br:11]>>[BrH:11].[CH3:7][O:8][CH2:9][CH2:10][N:6]1[CH:5]=[CH:4][S:3][C:2]1=[NH:1]
Reactant: COCCBr
Reactant: Nc1nccs1
Product: Br
Product: COCCn1ccsc1=N
Temperature: 85 °C
Yield: 72.5 %

Procedure:
A mixture of 2-aminothiazole (15 g, 0.15 mol) and 2-bromoethyl methyl ether (17 mL, 0.18 mol) were heated at 85° C. for 16 hours. After cooling to ambient temperature the resulting solid was triturated twice with isopropyl alcohol and collected by filtration to afford 26 g (72%) of the title compound. 1H NMR (DMSO-d6, 300 MHz) δ ppm 3.27 (s, 3H), 3.63 (t, J=5.1 Hz, 2H), 4.23 (t, J=4.9 Hz, 2H), 7.02 (d, J=4.7 Hz, 1H), 7.38 (d, J=4.4 Hz, 1H), 9.52 (s, 1H); MS (DCI/NH3) m/z 159 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[I:14][CH3:15]>C(O)C>[I-:14].[CH3:1][N+:2]1([CH3:15])[CH2:7][CH2:6][N:5]([CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:4][CH2:3]1
Reactant: CN1CCN(C2CCCCC2)CC1
Reactant: CI
Solvent: CCO
Product: C[N+]1(C)CCN(C2CCCCC2)CC1
Product: [I-]
Reaction time: 72 h
Yield: 95.9 %

Procedure:
A 50 mL flask was charged with 1.02 g of 1-methyl-4-cyclohexylpiperazine, 20 mL of anhydrous ethanol, and 0.88 g of iodomethane. After 3 days of stirring under a nitrogen atmosphere the solution was placed into a new flask and quenched with 200 mL ether producing a white crystalline solid. The solid was filtered and rinsed with additional ether and then dried in a vacuum oven overnight at 30° C. and −25 bar to give 1.74 g of 1,1-dimethyl-4-cyclohexylpiperazin-1-ium iodide.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.C([Li])(C)(C)C.[CH2:11]([Sn:15](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>C1COCC1>[CH2:20]([Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])[C:5]1[O:1][CH2:2][CH2:3][CH:4]=1)[CH2:21][CH2:22][CH3:23]
Reactant: C1=COCC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1=CCCO1
Reaction time: 0.25 h
Yield: 92.6 %

Procedure:
To a stirred solution of 0.35 ml (7.13 mmol) 2,3-dihydrofuran in 10 ml dry THF under argon at −78° C. was added 4.7 ml (7.2 mmol) tert-butyllithium solution (1.5M in pentane) and stirring continued for 5 minutes at −78° C. and 15 minutes at 0° C. The reaction mixture was then recooled to −78° C. and 1.92 ml (7.13 mmol) tributyltin chloride added dropwise and stirring continued for 16 hours at room temperature. The reaction mixture was partitioned between ether and water. The organic phase was then washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 2.37 g (93%) tributyl-(4,5-dihydro-furan-2-yl)-stannane as a yellow liquid which was used in the next step without further purification. EI-MS m/e (%): cluster at 303 ([M—C4H9]+, 100).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>C(OCC)(=O)C>[OH:13][C:14]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(C(C)(C)O)cc2)c2ncnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc(C(C)(C)O)cc2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 24.8 %

Procedure:
A mixture of hydroxylammonium chloride (0.97 g), sodium hydrogen carbonate (1.7 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({4-[4-(1-hydroxy-1-methylethyl)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.47 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.13 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.13 g, 24%).
Reaction SMILES: [C:1]1([S:7][CH2:8][C@H:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:17][C:16]=2[S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH2:10][C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:32]([N:34]([CH2:37][C@@H:38]1[CH2:43][O:42][CH2:41][CH2:40][N:39]1C(OC(C)(C)C)=O)[CH2:35][CH3:36])[CH3:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:32]([N:34]([CH2:37][C@H:38]1[N:39]([C:11](=[O:12])[CH2:10][C@@H:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:22])(=[O:23])=[O:24])=[CH:17][C:16]=2[S:25]([C:28]([F:29])([F:31])[F:30])(=[O:27])=[O:26])[CH2:8][S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:40][CH2:41][O:42][CH2:43]1)[CH2:35][CH3:36])[CH3:33]
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c(S(=O)(=O)C(F)(F)F)c1
Reactant: CCN(CC)C[C@@H]1COCCN1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCN(CC)C[C@@H]1COCCN1C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
To a solution of (R)-4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butanoic acid (INTERMEDIATE 8, 500 mg, 1.00 mmol), (R)—N-ethyl-N-(morpholin-3-ylmethyl)ethanamine hydrochloride salt (INTERMEDIATE 90, 209 mg, 1.00 mmol), DIPEA (0.701 ml, 4.01 mmol) in DMA (5 ml) was added HATU (458 mg, 1.20 mmol). The mixture was stirred for 1 h at room temperature and diluted with ethyl acetate (200 ml). The mixture was washed successively with 1M aq. sodium bisulfate, saturated sodium bicarbonate, and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified column chromatography (ISCO, eluting with 0→100% DCM/10% 2 M ammonia in MeOH in DCM over 24 minutes) to give the title product (200 mg, yield: 30.5%).