Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].N1C=CN=C1.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C)C=O>[CH3:15][C:16]([Si:19]([CH3:21])([CH3:20])[O:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.8 %

Procedure:
To a solution of 3-cyanophenol (5 g, 42 mmol) and imidazole (6.3 g, 92 mmol) in N,N-dimethylformamide (85 mL) at 0° C. was added (1,1-dimethylethyl)dimethylsilylchloride (7.6 g, 50 mmol). After stirring 10 min, the reaction was warmed to room temperature and stirred for 24 h. The solvent was removed in vacuo and the residual oil was partitioned between water (100 mL) and diethyl ether (300 mL). The separated diethyl ether layer was washed with water (3×100 mL) and brine (100 mL), then was dried (MgSO4) and filtered. The filtrate was evaporated under reduced pressure and the residue was flash chromatographed (silica gel, 50% ethyl acetate in petroleum ether) to yield 3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzonitrile (9 g, 92% yield) as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:15][CH2:14][CH2:13][C:3]1[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6][C:2]=1[CH3:1])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Reaction time: 0.25 h

Procedure:
2-(5-Methyl-2-phenyloxazol-4-yl)ethanol (20 g) and triethylamine (19.2 ml) were added to methylene chloride (200 ml) and, after dropwise addition of methanesulfonyl chloride (9.52 ml) at 0° C., the mixture was stirred at the same temperature for 15 min. The reaction mixture was washed with 10% aqueous citric acid solution (200 ml), saturated aqueous sodium hydrogen carbonate (100 ml) and saturated brine (100 ml), and dried (Na2SO4). Methylene chloride was evaporated under reduced pressure and the obtained residue was purified by column chromatography to give the title compound (21.45 g). 1H-NMR (CDCl3) δ (ppm); 2.53 (3H, s), 2.94 (3H, s), 2.94 (2H, t, J=7.0 Hz), 4.52 (2H, t, J=7.0 Hz), 7.30-7.50 (3H, m), 7.80-8.10 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][OH:6]
Reactant: O=Cc1cc(F)cc(Br)c1
Solvent: CO
Product: OCc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromo-5-fluorobenzaldehyde(22.25 g, 0.11 mole) in methanol at rt was added NaBH4,(2.07 g, 0.055 mole) stirred at rt for 2 hr. The reaction was quenched with H2O, and concentrated. The residue was diluted with diethyl ether, washed with 1 N HCl, brine, dried over MgSO4, and concentrated. 3-Bromo-5-fluorobenzyl alcohol was obtained as a colorless oil was collected (14.6 g, 65%). 1H NMR (DMSO-d6) δ4.50 (m, 2H), 5.44(t, 3H, J=5.93 Hz), 7.16 (dd, 1H, J=1.09, 8.79 Hz), 7.36(s, 1H), 7.38 (dd, 1H, J=2.99, 6.15 Hz); Anal. Calc. For C7H6Br2FO: C, 41.01, H, 2.95. Found: C, 41.30, H, 3.01.
Reaction SMILES: CO.[BH4-].[Na+].[N+:5]([N:8]1[C:12]2=[C:13]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C:14]3[CH:15]=[CH:16][C:17]([N:52]=3)=[C:18]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:19]3[N:23]([N+:24]([O-])=O)[C:22]([C:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[C:28]4[N:39]=[C:31]([C:32]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[C:9]1[CH:10]=[CH:11]2)[CH:30]=[CH:29]4)=[CH:21][CH:20]=3)([O-])=O>[Pd].ClCCl>[NH2:24][N:23]1[C:19]2=[C:18]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:17]3[CH:16]=[CH:15][C:14]([N:52]=3)=[C:13]([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:12]3[N:8]([NH2:5])[C:9]([C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[C:31]4[N:39]=[C:28]([C:27]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)=[C:22]1[CH:21]=[CH:20]2)[CH:29]=[CH:30]4)=[CH:10][CH:11]=3
Reactant: O=[N+]([O-])n1c2ccc1c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc(c(-c4ccccc4)c4nc(c2-c2ccccc2)C=C4)n3[N+](=O)[O-])C=C1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Nn1c2ccc1c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc(c(-c4ccccc4)c4nc(c2-c2ccccc2)C=C4)n3N)C=C1
Yield: 96.2 %

Procedure:
A 2-l three-necked round bottomed flask was fitted with a condenser and a dropping funnel to add solid material. To this flask was added anhydrous dichloromethane (850-ml) and methanol (420-ml). To this organic solution was added 10% palladium on carbon (14.0 g), the mixture was stirred under an argon blanket, and then cooled in an ice bath. Sodium borohydride (4.0 g, mol) was added in small portions over about 30-min. Next the dinitrotetraphenylporphyrin (7.0 g, 0.01 mol) and solid sodium borohydride (14.0 g) were added in small portions over about 60-min. The reaction mixture was stirred under argon for 30 min. The reaction mixture was filtered through a layer of CELITE® (diatomateous earth of Johns Manville, Denver, Colo.) in a Buchner funnel and washed repeatedly with dichloromethane. The solvent was completely removed under reduced pressure to produce a crude residue. The residue was redissolved in dry dichloromethane to separate insoluble CELITE®, and filtered. The solvent was removed under reduced pressure and dried to produce a purified residue (6.2 g). This residue was flash chromatographed over silica using dichloromethane as eluent. The product obtained (0.6 g, 9.6% yield) was free of impurities. See FIG. 4.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][C:8]1[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][CH:9]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cccc(CO)n1
Solvent: ClCCl
Product: COC(=O)c1cccc(COS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulphonyl chloride (0.28 ml) was added at 0° C. to a solution of methyl 6-hydroxymethylpicolinate (500 mg), TEA (0.5 ml) in DCM (5 ml). The mixture was stirred at rt for 1 hour, then diluted with DCM (50 ml) and washed with water (2×30 ml). Organic layer dried, solvent removed under vacuum to give expected product methyl 6-((methylsulfonyloxy)methyl)picolinate (770 mg). 1H NMR (CDCl3) δ: 8.11 (d, 1H), 7.93 (t, 1H), 7.70 (d, 1H), 5.44 (s, 2H), 4.01 (s, 3H), 3.16 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.CN(C)C=O.C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([Cl:19])=[O:10])[CH2:4][CH2:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN1CCC(C(=O)O)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCC(C(=O)Cl)CC1
Temperature: 20 °C

Procedure:
A flask was flame dried and placed under a nitrogen atmosphere. 1-methylpiperidine-4-carboxylic acid (1 eq) in anhydrous methylene chloride added to flask and cooled to 20° C. in a water bath. Dimethylformamide added, then oxalyl chloride (1.4 eq) in methylene chloride. Reaction refluxed for 2 hours, brought to room temperature, concentrated and azeotroped with toluene to yield 1-methylpiperidine-4-carbonyl chloride as a light yellow fluffy solid. MS: MH+=162.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH:12]1([CH2:18]Br)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([CH2:18][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrCC1CCCCC1
Reactant: COC(=O)c1ccc(O)cc1
Product: COC(=O)c1ccc(OCC2CCCCC2)cc1
Yield: 63.4 %

Procedure:
Using the general method of Compound 80 Part A, methyl 4-hydroxybenzoate (3.0 g, 19.7 mmole) was reacted with cyclohexylmethyl bromide (2.8 mL, 20.1 mmole) to provide 3.1 g of methyl 4-cyclohexylmethoxybenzoate as a white crystalline solid, m.p. 62°-63° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]([OH:19])=[O:18].Cl>[OH-].[Na+]>[CH2:5]([O:4][C:2]([N:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]([OH:19])=[O:18])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
Benzyl chloroformate (29.7 g, 174 mmol) was added dropwise to a 0° C. solution of Pyrrolidine-2-carboxylic acid (20.0 g, 174 mmol) dissolved in 1N NaOH (350 mL). The solution was stirred at 0° C. for 30 mins. The solution was allowed to equilibrate to room temperature while stirring overnight. The solution was acidified to pH=3 by addition of 1M HCl. The resulting solution was extracted with ethyl acetate (3×300 mL). The organic layers were combined, dried over MgSO4 and concentrated under vacuo to afford 40.4 g (89%) of the crude product, pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester, as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.CN(C)C=O.[OH-].[NH4+]>O>[N:13]1([C:2]2[C:11]3[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: c1nc[nH]n1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc2c(-n3cncn3)ccnc2c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 69.8 %

Procedure:
A mixture of 1.98 g of 4,7-dichloro-quinoline, 1.38 g of 1,2,4-triazole and 10 ml of dimethyl formamide is stirred at 100° C. for 6 hours, whereupon the reaction mixture is poured into 100 ml of water and neutralized with 1 ml of a concentrated ammonium hydroxide solution. The precipitated product is filtered and recrystallized from ethanol. Thus 1.61 g of the desired product are obtained, yield 70%, Mp.: 169°-170° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([S:17]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]2[C:26](O)=[O:27])(=[O:19])=[O:18])[CH2:13][CH2:12]1.Cl.[CH2:30]([O:37][NH2:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN1CCOCC1.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:30]([O:37][NH:38][C:26]([C@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][N:20]1[S:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][CH:6]=2)[CH2:12][CH2:13]1)(=[O:18])=[O:19])=[O:27])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(NOCc1ccccc1)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (0.46 g, 1.12 mmol) [prepared as described Step 2 above] in methylene chloride (10 ml) was added O-benzylhydroxylamine hydrochloride salt (0.54 g, 3.36 mmol), followed by 4-dimethylaminopyridine (0.15 g, 1.23 mmol), 4-methylmorpholine (0.38 ml, 3.47 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.43 g, 2.24 mmol). The reaction was stirred at RT for 2 h, diluted with methylene chloride (50 ml) and washed with 1M HCl. The organic layer was washed with brine, dried over MgSO4, and concentrated to give N-benzyloxy-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (95%) as a clear oil. This material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]2O.O=P(Cl)(Cl)[Cl:21].P(Cl)(Cl)(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]2[Cl:21]
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1Cl

Procedure:
To a stirred solution of the crude 6-methoxy-4-hydroxy-3-ethoxycarbonylquinoline (Step A, 74 g, 0.25 M) in dry toluene (300 mL) was added POCl3 (46.6 mL, 0.5 mol) followed by PCl5 (26 g, 0.125 mol). The mixture was heated at reflux for 6 h. The toluene and the excess of POCl3 were removed under vacuum. The solid residue was suspended into a mixture of 1N NaOH and ice. The resulting solid was filtered off, washed several times with water, then with a minimum amount of MeOH, and dried over P2O5 to give 6-methoxy-4-chloro-3-ethoxycarbonylquinoline as a white solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[CH2:10][CH2:9][N:8]([C@H](C2C=CC=CC=2)C)[C@@H:7]1[C:19]([NH2:21])=[O:20])(=[O:3])[CH3:2].O>CO.[Pd]>[C:1]([NH:4][CH2:5][C@@H:6]1[CH2:10][CH2:9][NH:8][C@@H:7]1[C:19]([NH2:21])=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)NC[C@@H]1CCN([C@@H](C)c2ccccc2)[C@@H]1C(N)=O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(=O)NC[C@@H]1CCN[C@@H]1C(N)=O

Procedure:
A mixture of (2S,3S)-3-(acetylamino-methyl)-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid amide (Stage 36.2) (0.48 mmol) and 10% Pd on charcoal, wet with 50% H2O (Aldrich 330108) (0.096 mmol) in MeOH (5 mL) was hydrogenated for 6.5 h at rt. The reaction mixture was then filtered through a Fluoropore Membrane Filter (0.2 μm FG) and evaporated. The residue was dissolved in CH2Cl2 and evaporated to dryness to afford the title compound as an off-white solid. ESI-MS: [M+H]+ 186; TLC: Rf=0.08 (200:20:1 CH2Cl2/MeOH/conc. NH4OH).
Reaction SMILES: C([N:11]1[CH2:18][C:17](=[O:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.[BrH:20].CCOCC>C(O)(=O)C>[BrH:20].[O:19]=[C:17]1[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1
Reactant: O=C1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C1CN[C@H](C(=O)O)C1
Reaction time: 0.13 h

Procedure:
To 4.0 g. (0.015 mole) of N-carbobenzyloxy-4-keto-L-proline are added 20 ml. of hydrogen bromide in acetic acid (30-32%). The mixture is frequently swirled over a period of eight minutes. At the end of this period (effervescence has stopped), the yellow-orange solution is layered over with 25° of ether, triturating the gummy product. The ether is discarded and the resulting tacky solid is triturated with fresh ether and finally with 50 ml. of acetonitrile to give 4-keto-L-proline, hydrobromide as a crystalline solid weighing 2.7 g. (85%), m.p. 153°-155° (dec.,), [α]D26 -49° (c, 1% in water).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=O)[CH:3]=1>C1COCC1.[Pt]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:6])=[CH:7][CH:8]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: C1CCOC1
Product: Nc1ccc(Br)cc1N
Reaction time: 2 h

Procedure:
4-Bromo-2-nitroaniline (10 g, 46 mmol) in THF (120 mL) was treated with 1% Pt/C (1.0 g) and hydrogenated at room temperature under 40 psi of H2 pressure. After 2 hours, the reaction was filtered and the filtrate concentrated to provide the title compound which was used without further purification in the next step. MS 188 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 6.77-6.81 (m, 2H), 6.54 (d, J=8.4 Hz, 1H), 3.28 (br, 4H).
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C:10]#[CH:11])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[C:12]([O:15][CH:16]([CH2:21][O:22][S:23]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:17][N:18]=[N+:19]=[N-:20])(=[O:14])[CH3:13]>>[C:12]([O:15][CH:16]([CH2:21][O:22][S:23]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:17][N:18]1[CH:11]=[C:10]([CH2:9][N:5]2[CH:6]=[CH:7][N:8]=[C:4]2[N+:1]([O-:3])=[O:2])[N:20]=[N:19]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(CN=[N+]=[N-])COS(=O)(=O)c1ccc(C)cc1
Reactant: C#CCn1ccnc1[N+](=O)[O-]
Product: CC(=O)OC(COS(=O)(=O)c1ccc(C)cc1)Cn1cc(Cn2ccnc2[N+](=O)[O-])nn1

Procedure:
2-Nitro-1-(prop-2-ynyl)-1H-imidazole 10 (0.2 g, 1.32 mmol) is heated with 1-azido-3-(tosyloxy)propan-2-yl acetate 15 (0.41 g, 1.32 mmol) at 60° C. overnight. The residue is purified by chromatography on silica gel (MeOH/CH2Cl2, 1:10) to afford 16.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1.CC(C)([O-])C.[K+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:2][CH2:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10]1
Reactant: C=Cc1ccccn1
Reactant: C1=Cc2ccccc2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C1=C(CCc2ccccn2)c2ccccc2C1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
43 g (0.47 mol) of 2-vinylpyridine were added to a mixture of 56 ml (0.48 mol) of indene in 40 ml of toluene and 4 g (0.036 mol) of solid potassium tert-butoxide at 60-90° C. over a period of 40 minutes. The mixture was then stirred for another 2 hours at 115° C., cooled to room temperature and subsequently neutralized by means of 2 ml of glacial acetic acid. Insoluble constituents were filtered off and the filtrate was distilled under reduced-pressure. This gave 42 g of 2-[2-(1H-inden-3-yl)ethyl]pyridine (40%, b.p. 161-163° C. at 2 mm).
Reaction SMILES: Br[CH:2]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].C(N(CC)CC)C>CC(C)=O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:3]([S:4]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)(=[O:6])=[O:5])=[CH:2][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C(=O)C(Br)C(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccccc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)C=C(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccccc1
Temperature: 0 °C
Yield: 60.2 %

Procedure:
A solution of 9.6 g of 2-bromo-1-(2,4-dichlorophenyl)-4,4-dimethyl-1-phenylsulfonylpentan-3-one and 2.23 g of triethylamine in 100 ml of acetone was refluxed for 3 hours. The mixture was poured into ice water and extracted with 150 ml of ethyl acetate. The organic layer was washed twice with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of n-hexane (20 parts) and acetone (1 part) to give 4.8 g of 1-(2,4-dichlorophenyl)-4,4-dimethyl-1-phenylsulfonyl-1-penten-3-one. nD25 1.5723
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(=O)(O)[O-].[Na+].[CH:10]1[C:22]2[CH:21]([CH2:23][O:24][C:25](Cl)=[O:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1>O1CCCC1.O>[CH:10]1[C:22]2[CH:21]([CH2:23][O:24][C:25](=[O:26])[NH:4][CH2:3][CH2:1][OH:2])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: NCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCO)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
To a stirred mixture of ethanolamine (0.49 g, 8 mmol), tetrahydrofuran, water and sodium bicarbonate (1.5 g, 18 mmol) at 6° C., was added a solution 9-fluorenylmethylchloroformate (2.27 g, 8.8 mmol) in tetrahydrofuran in one portion, stirring was continued for 1 h allowing the mixture to warm to room temperature. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate filtered and evaporated to a crude product. The crude product was re-crystallised from dichloromethane to give (2-hydroxy-ethyl)-carbamic acid 9H-fluoren-9-ylmethyl ester as a white solid (1.2 g).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].CC(C)[O-].[Ti+4:15].CC(C)[O-].CC(C)[O-].CC(C)[O-]>C1(C)C=CC=CC=1>[C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Ti+4:15].[C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(O)c1ccccc1O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: O=C([O-])c1ccccc1O
Temperature: 100 °C

Procedure:
A solution of salicylic acid (27.6 g, 200 mmol) and toluene (220 ml) was dehydrated by distilling 20 mL of the solution. Thereafter, 28.4 g (100 mmol) of titanium(IV) isopropoxide (TTIP) was added to the solution while stirring. The mixed solution was refluxed for 1 hour, and then, while the distillation temperature was 100° C. or higher, distilled until the amount of the solution became half. After the distillation, solid content of the product was isolated by suction filtering using a membrane suction filter. The residual solid content was heated to 100° C. under vacuum using a vacuum dryer so that remaining volatile components were completely removed. The solid content (salicylic acid-titanium complex) was red in color. The yield amount was 32.0 g (100 mmol), and the yield percentage was 100%. 3.20 g of salicylic acid-titanium complex was dissolved into 100 mL of 1:4 acetylacetone/toluene to produce a coating liquid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([OH:16])[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1.[Br:17]N1C(=O)CCC1=O>CN(C=O)C>[Br:17][C:5]1[S:1][C:2]([C:6]2([OH:16])[CH2:7][CH2:8][C:9]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:14][CH2:15]2)=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OC1(c2nccs2)CCC2(CC1)OCCO2
Solvent: CN(C)C=O
Product: OC1(c2ncc(Br)s2)CCC2(CC1)OCCO2
Temperature: 50 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
The product of Step 1 (60.5 g, 251 mmol) was diluted with DMF (365 mL). N-bromosuccinimide (49.1 g, 276 mmol) was added, and the solution was heated to 50° C. and stirred for 2 h. The reaction was removed from heat and cooled to 45° C. and H2O (600 mL) containing 15.8 g Na2SO3 was added dropwise affording a solid. The mixture was stirred at room temperature for 1 h, then filtered and washed 2× with H2O (300 mL). The cake was dried overnight under a nitrogen bag to afford 8-(5-bromo-1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (68.2 g; 85%) as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:8][CH2:9][C:10]1[C:11]([F:18])=[C:12]([C:14]([F:17])=[CH:15][CH:16]=1)[NH2:13]>C1COCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[NH2:13][C:12]1[C:11]([F:18])=[C:10]([CH:16]=[CH:15][C:14]=1[F:17])[CH2:9][NH:8][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1ccc(F)c(N)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(F)c(N)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TEA (400 μL, 2.86 mmol) followed by pivaloyl chloride (60 μL, 0.52 mmol) are added to 3-aminomethyl-2,6-difluoro-aniline (120 mg as HCl salt) in THF (10 mL) and stirred at rt overnight. The reaction mixture is diluted with EtOAc and sat. NaHCO3-solution, the organic layer is washed with water and brine, dried and concentrated to give the sub-title compound.