Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][C:10]2([CH2:13][CH:12]([N:14]3[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]3)[CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][C:27]1([NH2:31])[CH2:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:26][C:27]1([NH:31][C:20]([CH:17]2[CH2:16][CH2:15][N:14]([CH:12]3[CH2:13][C:10]4([CH2:23][CH2:24][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]4)[CH2:11]3)[CH2:19][CH2:18]2)=[O:22])[CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(N3CCC(C(=O)O)CC3)C2)C1
Reactant: CC1(N)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(NC(=O)C2CCN(C3CC4(CCN(C(=O)OC(C)(C)C)C4)C3)CC2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
1-[6-(tert-Butoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidine-4-carboxylic acid was dissolved in DMF (5 mL) and (1-methylcyclobutyl)amine hydrochloride (0.37 g, 3.03 mmol), HATU (0.844 g, 2.22 mmol) and DIPEA (1.305 g, 10.1 mmol) were added. The reaction mixture was stirred at rt overnight under nitrogen. The solvents were removed in vacuo, and the residue was partitioned between DCM and sat. NaHCO3 sol., organic layer washed with sat. NaCl sol. and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 50 g, 40-63 μm, 60 A, 50 mL per min, gradient 0% to 10% MeOH in DCM]) to give tert-butyl 2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.627 g, 76.7%) as a white foam.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][N:6]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2[NH:14][C:15]([CH:18]=O)=[C:16]([CH3:17])[C:8]=2[C:7]1=[O:20])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2.N1CCCCC1>C(O)C>[CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][N:6]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2[NH:14][C:15](/[CH:18]=[C:27]3\[C:28](=[O:33])[NH:29][C:30]4[C:26]\3=[CH:25][C:24]([F:23])=[CH:32][CH:31]=4)=[C:16]([CH3:17])[C:8]=2[C:7]1=[O:20])[CH3:2]
Reactant: CCN(CC)CCN1CCCCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCN1CCCCc2[nH]c(/C=C3\C(=O)Nc4ccc(F)cc43)c(C)c2C1=O
Temperature: 25 °C
Yield: 48.4 %

Procedure:
5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7,8,9-hexahydro-1H-1,5-diaz a-cyclopentacyclooctene-2-carbaldehyde 60e (20 mg, 0.066 mmol) was dissolved in 1 ml of ethanol under stirring, and added with 5-fluoro-1,3-dihydro-indol-2-one (9.9 mg, 0.066 mmol) to the solution at room temperature. The reaction mixture was stirred in dark until dissolved, added with 0.1 ml of piperidine, and heated to reflux for 2 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled down to room temperature, filtered to obtain the title compound (Z)-5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-6,7,8,9-tetrahydro-1H,5H-1,5-diaza-cyclopentacycloocten-4-one 60 (14 mg, yield 48.8%) as a yellow solid.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:15][C:10]=2[N:9]=[CH:8]1.[I:22]N1C(=O)CCC1=O>CCCCCC.C1COCC1>[I:22][C:8]1[N:7]([CH3:6])[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:15][C:10]=2[N:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cn1cnc2cc(CN3CCCC3)ccc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1c(I)nc2cc(CN3CCCC3)ccc21
Reaction time: 0.17 h

Procedure:
0.80 mL (1.28 mmol) 1.6 M n-butyllithium solution in hexane are added to a solution, cooled to −75° C., of 250 mg (1.16 mmol) 1-methyl-5-pyrrolidin-1-ylmethyl-1H-benzimidazole in 8 mL THF. The reaction mixture is stirred for 10 min at this temperature and then 288 mg (1.28 mmol) N-iodosuccinimide in 5 mL THF are added. The cooling bath is removed and the reaction stirred for 1 h at RT. 12 mL 0.1 M HCl are added and the aqueous phase is extracted with EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography on silica gel (gradient: DCM to DCM/MeOH/NH3 9:1:0.1).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][OH:8].O[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][N:10]1[C:14](=[O:15])[C:13]2[C:12](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]1=[O:20]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCc1ncc[nH]1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCc1ncc[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 6.6 %

Procedure:
To an ice-cold solution of (1H-imidazol-2-yl)methanol hydrochloride (2.0 g, 15 mmol), N-hydroxyphthalimide (2.4 g, 15 mmol) and triphenylphosphine (4.0 g, 15 mmol) in THF (65 mL) was added a solution of diethyl azodicarboxylate (2.6 mL, 16 mmol) in THF (10 mL) dropwise. The stirred reaction mixture was allowed to warm to ambient temperature. After 1 day, most of the THF was removed under reduced pressure. The residue was partitioned between CH2Cl2 (75 ml) and H2O (30 mL). The organic layer was separated and washed with saturated NaHCO3 (75 mL) and saturated NaCl (20 ml), dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (silica gel, CH2Cl2 to 95:5 CH2Cl2/MeOH) gave 2-(1H-imidazol-2-ylmethoxy)-1,3-dihydro-2H-isoindole-1,3-dione (240 mg, 6.5%) which was used directly in the next reaction.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:9]1[CH:19]=[CH:18][C:12]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C([O-])([O-])=O.[K+].[K+].Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(#N)C>[CH2:32]([O:31][C:29]([N:13]([S:14]([CH3:17])(=[O:15])=[O:16])[C:12]1[CH:18]=[CH:19][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:20])[F:21])=[CH:10][CH:11]=1)=[O:30])[CH3:33]
Reactant: CCOC(=O)Cl
Reactant: CS(=O)(=O)Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N(c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)S(C)(=O)=O
Reaction time: 16 h

Procedure:
To 6.7 g (20 mmole) 4'-(hexafluoro-2-hydroxy-2-propyl)-methanesulfonanilide (prepared as in Example 1) in 100 ml acetonitrile, add 4.1 g (30 mmole) K2CO3 and 2.2 g (20 mmole) ethyl chloroformate. Stir 16 hours, filter and concentrate. Partition the residue between Et2O and 5% Na2CO3. Dry, concentrate and recrystallize first from Et2O-hexane and then from toluene to give the product; m.p. 108°-112° C.
Reaction SMILES: [C:1]([C:3]1[N:7]([C@@H:8]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]2[OH:10])[CH:6]=[N:5][C:4]=1[C:17]#[N:18])#[CH:2].[OH:19]O>N.CO>[C:1]([C:3]1[N:7]([C@@H:8]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]2[OH:10])[CH:6]=[N:5][C:4]=1[C:17]([NH2:18])=[O:19])#[CH:2]
Reactant: OO
Reactant: C#Cc1c(C#N)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: N
Solvent: CO
Product: C#Cc1c(C(N)=O)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 127 mg (0.51 mmol) of 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carbonitrile dissolved in 6 ml of a solvent mixture of aqueous ammonia and methanol (1:1) was added 0.5 ml of hydrogen peroxide, and the reaction was carried out with stirring at room temperature for 45 minutes. After the reaction, the solvent was evaporated, and the residue was adsorbed onto chloroform solvent mixture, and crystallized from ethanol to obtain white crystals of 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25]>>[OH:25][CH2:24][C:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])([CH3:27])[CH3:26]
Reactant: CC(C)(N)CO
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CC(C)(CO)Nc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Yield: 39 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 2-amino-2-methyl-propan-1-ol according to the GPA affording 14.2 mg (39%) of a red powder. Rt=3.55 min.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[O-]CC.[Na+].[CH:21]12[O:27][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26]2.Cl>C(O)C>[CH3:13][C:12]([C:7]1[CH:8]=[C:9]([S:11][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[OH:27])[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[OH:16])([CH3:15])[CH3:14]
Reactant: C1CCC2OC2C1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2,6-bis(1,1-Dimethylethyl)-4-mercaptophenol (12.8 g, 0.054 moles) was added to a solution of sodium ethoxide [prepared from sodium (2.5 g 0.108 mole)] in ethyl alcohol (75 ml). Cyclohexene oxide (5.15 g, 0.0525 mole) was added and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into 10% hydrochloric acid (250 ml) and the mixture was extracted twice with 200ml of ethyl ether. The combined ethyl ether extracts were washed twice with 25 ml of water, dried over magnesium sulfate, filtered and concentrated in vacuo to a yellow oil. The product was purified by silica get chromatography and recrystallized from methyl alcohol/water, m.p. ca 91° C. The structure was supported by NMR, infrared spectroscopy, and elemental analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:16])([CH3:15])[C:7](=[O:14])[N:8]2[CH:11]2[CH2:13][CH2:12]2)=[CH:4][C:3]=1[F:17].[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][N:27]=1)[C:22](O)=[O:23]>>[CH:11]1([N:8]2[C:9]3[C:5](=[CH:4][C:3]([F:17])=[C:2]([NH:1][C:22](=[O:23])[C:21]4[CH:25]=[CH:26][N:27]=[C:19]([CH3:18])[CH:20]=4)[CH:10]=3)[C:6]([CH3:15])([CH3:16])[C:7]2=[O:14])[CH2:13][CH2:12]1
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)c(F)cc21
Product: Cc1cc(C(=O)Nc2cc3c(cc2F)C(C)(C)C(=O)N3C2CC2)ccn1

Procedure:
Prepared in analogy to example 26 from 6-amino-1-cyclopropyl-5-fluoro-3,3-dimethyl-1,3-dihydro-indol-2-one and 2-methylisonicotinic acid. The title compound was obtained as light yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.[N:18]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>Cl.O1CCCC1.O>[Br:17][C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[NH:1][N:18]=[C:4]2[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Br)cc1C(=O)c1ccc(F)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(-c2n[nH]c3ccc(Br)cc23)cc1
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
To a solution of 2-amino-5-bromo-4′-fluorobenzophenone (13.50 g, 45.9 mmol) in 6 N hydrochloride solution (400 mL) and tetrahydrofuran (500 mL) at −15° C. was slowly dropped a solution of sodium nitrite (4.12 g, 59.7 mmol) in water (20 mL). After stirring for 30 minutes in cold bath, to the reaction mixture was added a solution of tin(II) chloride dihydrate (28.48 g, 126 mmol) in concentrated hydrochloric acid (70 mL) dropwise. A white solid precipitated immediately. After 30 minutes, the white solid was filtered, dissolved in ethyl acetate, and washed with saturated sodium bicarbonate. The filtrate was neutralized with sodium hydroxide and extracted with dichloromethane. The ethyl acetate and dichloromethane layers were combined, dried over magnesium sulfate, and concentrated. Crystallization from ethyl acetate gave the title compound as a white solid (5.266 g). The mother liquor was then purified by chromatography (SiO2, 15–30% ethyl acetate/hexane) to provide another batch of the title compound (3.429 g, total 8.695 g, 65% yield). 1H NMR (CDCl3) δ 10.54 (br s, 1H), 8.11 (m, 1H), 7.87–7.92 (m, 2H), 7.50 (m, 1H), 7.34 (d, 1H), 7.20–7.26 (m, 2H); ES-MS (m/z) 293 [M+3]+, 291 [M+1]+.
Reaction SMILES: [C:1]([OH:11])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:34][CH2:35][C:36]1[N:40]([C:41]2[S:42][C:43]([CH2:55][CH3:56])=[CH:44][C:45]=2[C:46](=[O:54])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[Cl:53])[C:39]([CH3:57])=[N:38][N:37]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C:46]([C:45]1[CH:44]=[C:43]([CH2:55][CH3:56])[S:42][C:41]=1[N:40]1[C:39]([CH3:57])=[N:38][N:37]=[C:36]1[CH2:35][NH:34][C:1](=[O:11])/[CH:2]=[CH:3]/[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:54]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Reactant: O=C(O)/C=C/c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)/C=C/c2ccccc2)s1
Reaction time: 24 h
Yield: 66.3 %

Procedure:
trans-Cinnamic acid (1.48 g), 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (7.42 g) and triethylamine (5.6 ml) were dissolved in dimethylformamide (50 ml). 1-Benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (Bop reagent, 4.42 g) was added, and the mixture was stirred for one day. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated to give 5.05 g of crude crystals. The crystals were recrystallized from ethyl acetate to give 3.25 g of trans-N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-3-phenylacrylamide.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[C@@H:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH2:4]O.C(N(CC)CC)C.CS([Cl:29])(=O)=O>C(Cl)Cl>[Cl:29][CH2:4][C@H:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH:2]([CH3:17])[CH3:1]
Reactant: CC(C)[C@H](CO)Nc1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](CCl)Nc1ccc(C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
(2R)-3-Methyl-2-{[4-(trifluoromethyl)phenyl]amino}butan-1-ol (1.67 g, 6.76 mmol) obtained in Step 1 was dissolved in methylene chloride (30 mL) and triethylamine (1.20 mL, 8.67 mmol), and methanesulfonyl chloride (0.63 mL, 8.14 mmol) was added dropwise under cooling. After stiring overnight, the mixture was worked-up according to a conventional method to give N-[(1R)-1-(chloromethyl)-2-methylpropyl]-4-(trifluoromethyl)aniline as a crude product. The obtained crude product was dissolved in dimethylformamide (20 mL), sodium azide (0.40 g, 6.15 mmol) was added, and the mixture was stirred overnight at 80° C. The solvent was evaporated, and the residue was worked-up according to a conventional method to give a crude product. The obtained crude product was dissolved in ethyl acetate (20 ml), 10% palladium/carbon (catalytic amount) was added, and the system was purged with hydrogen. The mixture was stirred overnight at room temperature, palladium/carbon was filtered off, and the solvent was evaporated to give the title compound (1.50 g, 6.09 mmol, 90%).
Reaction SMILES: C([SiH](CC)CC)C.[C:8]([C:12]1[C:17]2[CH:18]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:20][C:16]=2[CH:15]=[CH:14][C:13]=1[OH:29])([CH3:11])([CH3:10])[CH3:9].FC(F)(F)C(O)=O>>[C:8]([C:12]1[C:17]2[CH2:18][CH:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:20][C:16]=2[CH:15]=[CH:14][C:13]=1[OH:29])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCCCCCCCc1cc2c(C(C)(C)C)c(O)ccc2o1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCC1Cc2c(ccc(O)c2C(C)(C)C)O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.8 %

Procedure:
Triethylsilane (2.8 ml) was added to 4-tert-butyl-5-hydroxy-2-octylbenzofuran (300 mg, 1.0 mmol) and, then, trifluoroacetic acid (1.4 ml) was added dropwise under ice cooling. The mixture was stirred first at 0° C. for 15 min, then at room temperature for 1 h. Thereafter, the mixture was poured into ice water and subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (chloroform) to afford 4-tert-butyl-5-hydroxy-2-octyl-2,3-dihydrobenzofuran [252 mg (yield, 83%)] as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([NH:17][NH2:18])[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:26]1([CH2:29][C:30](Cl)=[O:31])[CH2:28][CH2:27]1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][N:12]=[C:13]([NH:17][NH:18][C:30](=[O:31])[CH2:29][CH:26]2[CH2:28][CH2:27]2)[C:14]=1[C:15]#[N:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c(OCc2ccccc2)ccnc1NN
Reactant: O=C(Cl)CC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1c(OCc2ccccc2)ccnc1NNC(=O)CC1CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.9 %

Procedure:
To a solution of intermediate compound D3 (4.099 g, 17.06 mmol) in dry DCM (112 ml) were added triethylamine (2.76 g, 27.294 mmol) and cyclopropyl-acetyl chloride (3.438 g, 29 mmol). The resulting reaction mixture was stirred at r.t. for 20 min, then concentrated in vacuo to yield intermediate compound D4 (5 g, 91%), which was used without further purification.
Reaction SMILES: O[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.CS([Cl:31])(=O)=O>>[Cl:31][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(NCc1ccc(CO)cc1)c1ccccn1
Solvent: CCN(CC)CC
Product: O=S(=O)(NCc1ccc(CCl)cc1)c1ccccn1
Yield: 45.2 %

Procedure:
Reaction of pyridine-2-sulfonic acid 4-hydroxymethyl-benzylamide (140 mg, 0.50 mmol), Et3N (88 μL, 0.60 mmol), and MsCl (47 μL, 0.60 mmol) for 2 h at reflux followed by column chromatography on silica gel (CH2Cl2/MeOH 99:1) gave the title compound (67 mg, 45%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 4.28 (d, 2H, J=6.0 Hz), 4.54 (s, 2H), 5.17 (br s, 1H), 7.23-7.49 (m, 4H), 7.47-7.52 (m, 1H), 7.88 (ddd, 1H, J=7.5, 7.5, 1.7 Hz), 7.97 (d, 2H, J=7.5 Hz), 8.69 (d, 1H, J=4.8 Hz). ES-MS m/z 319 (M+Na).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[C:17]1[C:32]([NH2:34])=[O:33].CO>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:14])[NH:31][C:28]1[CH:27]=[CH:26][C:25]([C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]([CH3:15])[C:17]=2[C:32]([NH2:34])=[O:33])=[CH:30][CH:29]=1
Reactant: Cn1c(C(N)=O)c(-c2ccc(N)cc2)c2ccccc21
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(C(N)=O)c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2ccccc21
Reaction time: 1 h
Yield: 59 %

Procedure:
0.075 g of 2-fluoro-5-trifluoromethylphenyl isocyanate is added to a solution of 0.086 g of 1-methyl-3-(4-aminophenyl)-1H-indole-2-carboxamide in 18 ml of tetrahydrofuran and the stirring is continued for 1 hour. 5 ml of methanol are added, the reaction mixture is then concentrated under reduced pressure, and the residue is purified by chromatography on a silica column, elution being carried out with a mixture of cyclohexane and ethyl acetate (20/80 by volume), to give 90 mg of 3-{4-[3-(2-fluoro-5-trifluoromethyl-phenyl)ureido]phenyl}-1-methyl-1H-indole-2-carboxamide, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9](C(=O)C(F)(F)F)[CH2:8][CH:7]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH:29]([CH3:31])[CH3:30])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[C:6]=2[CH:5]=[C:4]([O:32][CH3:33])[C:3]=1[O:34][CH3:35].[OH-].[Na+].CO>O>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([C:19]3[CH:20]=[CH:21][C:22]([S:25]([CH2:28][CH:29]([CH3:31])[CH3:30])(=[O:27])=[O:26])=[CH:23][CH:24]=3)[C:6]=2[CH:5]=[C:4]([O:32][CH3:33])[C:3]=1[O:34][CH3:35]
Reactant: COc1cc2c(c(Cl)c1OC)CCN(C(=O)C(F)(F)F)CC2c1ccc(S(=O)(=O)CC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(c(Cl)c1OC)CCNCC2c1ccc(S(=O)(=O)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
A mixture of 8.9 g (0.015 m) of the amide, 1 g (0.025 m) of sodium hydroxide and 100 ml of methanol was stirred at room temperature for 2 hours, then, poured into water. The quench was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give 4.4 g of 6-chloro-1-(4'-isobutylsulfonylphenyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26](=O)[CH2:27][CH3:28])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.Cl.[NH:31]1[CH2:34][CH:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:26]([N:31]2[CH2:34][CH:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32]2)[CH2:27][CH3:28])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:19][CH2:18]1)[N:11]=2
Reactant: COC(=O)C1CNC1
Reactant: CCC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Product: CCC(c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)N1CC(C(=O)OC)C1

Procedure:
Reaction of 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)propan-1-one (0.200 g, 0.497 mmol) and methyl azetidine-3-carboxylate hydrochloride (0.113 g, 0.745 mmol), according to reference R and the general procedure for reductive amination gave racemic methyl 1-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)propyl)azetidine-3-carboxylate. Separation of enantiomers was accomplished by SFC chromatography (Column: Chiralpak AD-H (21×250 mm, 5 um); A: Liquid CO2; B: Isopropanol (0.2% DEA); Isocratic: 79:21 (A:B); Flow Rate: 70 mL/min; Outlet Pressure: 100 bar) to give (R)-methyl 1-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)propyl)azetidine-3-carboxylate and (S)-methyl 1-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)propyl)azetidine-3-carboxylate. MS (ESI) m/z: Calculated: 501.2; Observed: 502.1 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]2[N:9]([CH3:19])[CH:10]=[C:11]([C:14](OCC)=[O:15])[C:12](=[O:13])[C:7]=2[S:6][CH:5]=1)[CH3:2].[NH3:20]>C(O)C>[CH2:1]([O:3][C:4]1[C:8]2[N:9]([CH3:19])[CH:10]=[C:11]([C:14]([NH2:20])=[O:15])[C:12](=[O:13])[C:7]=2[S:6][CH:5]=1)[CH3:2]
Reactant: CCOC(=O)c1cn(C)c2c(OCC)csc2c1=O
Reactant: N
Solvent: CCO
Product: CCOc1csc2c(=O)c(C(N)=O)cn(C)c12
Temperature: 25 °C

Procedure:
Ethyl 3-ethoxy-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate (3 g) and a saturated solution of ammonia in ethanol (70 ml) were stirred together in a sealed stainless steel pressure vessel at 130° for 24 hours. After allowing to cool to ambient temperature the mixture was filtered and the solid was dried to give the novel compound 3-ethoxy-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide, m.p. 286°-287°.