Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S([N:9]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:10]2[C:18]([O:20][CH3:21])=[O:19])=O)=CC=1.FC(F)(F)C(O)=[O:26]>C(#N)C>[NH2:9][C@@H:10]([C@@H:11]([OH:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)[C@@H]1[C@H](c2ccccc2)N1S(=O)c1ccc(C)cc1
Solvent: CC#N
Product: COC(=O)[C@@H](N)[C@@H](O)c1ccccc1
Temperature: 45 °C
Reaction time: 6 h

Procedure:
Into a 50-mL round-bottomed flask equipped with a magnetic stir bar were placed 0.315 g (1.0 mmol) (2S,3S)-(+)-N-(p-toluenesulfinyl)-2-carbomethoxy-3-phenylaziridine (prepared according to Example 1), 10 mL acetonitrile and 2 mL 50% aqueous trifluoroacetic acid. The reaction mixture was stirred for 6 h at 45° C., the solvent was removed and the residue treated with H2O (5 mL). After washing the aqueous solution with ether (2×10 mL), the aqueous phase was brought to pH 10 with concentrated NH4OH and extracted with CHCl3 (2×10 mL). After drying (MgSO4), the organic phase was filtered and concentrated to give the titled compound in impure form, which was purified by flash chromatography (ether:CH3CN:NH4OH; 10:1:0.2) to afford the titled compound (0.138 g, 71%) as a viscous oil: [α]D20 +11.0° (c 1.8, MeOH) ([α]D20 -10.97° (c 1.4, MeOH) according to Beulshausen, T. et al. Liebigs Ann. Chem. 1991, 1207 for the (2R,3S)-isomer); 1H NMR (CDCl3) δ2.10 (bs, 3H, NH2, OH) 3.65 (d, J=4.5 Hz, 1H, CH), 3.69 (s, 3H, CH3), 4.91 (d, J=4.5 Hz, 1H, CH) 7.36-7.26 (m, 5H, aromatic); 13C NMR (CDCl3) δ52.2, 60.6, 74.1, 126.0, 127.8, 128.4, 140.9, 173.7.
Reaction SMILES: [CH3:1][C:2]1([CH2:9][CH3:10])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[Cl:17][CH2:18][CH2:19]Cl>CN(C)C=O>[Cl:17][CH2:18][CH2:19][N:4]1[C:3](=[O:8])[C:2]([CH3:1])([CH2:9][CH3:10])[NH:6][C:5]1=[O:7]
Reactant: CCC1(C)NC(=O)NC1=O
Reactant: ClCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1(C)NC(=O)N(CCCl)C1=O
Reaction time: 25 h

Procedure:
284.3 g of 5-methyl-5-ethyl-hydantoin (2.0 mols), 138.2 g of anhydrous potassium carbonate (1.0 mol), 791.7 g of 1,2-dichloroethane (8.0 mols) and 230 ml of dimethylformamide are subjected to an azeotropic circulatory distillation, analogously to A, for 25 hours at 90° C to 107° C internal temperature (external temperature: 160° C). After completion of the reaction, the mixture is filtered whilst still hot and the filtrate is concentrated on a rotary evaporator at 90° C under a water pump vacuum. The reaction mixture is then dried to constant weight at 90° C and 10-1 mm Hg. 392.5 g of a brown, clear product (95.9% of theory) are obtained, and purified by vacuum distillation (boiling point0.2 : 147° C). Yield of pure material: 327.3 g (80% of theory). A sample recrystallised from diethyl ether melts at 58.0° C to 59.0° C.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:34])(=[O:3])[CH3:2].[CH3:35][C@@H:36]1[CH2:40][O:39][C:38](=[O:41])[NH:37]1>>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:37]3[C@H:36]([CH3:35])[CH2:40][O:39][C:38]3=[O:41])[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:34])(=[O:3])[CH3:2]
Reactant: C[C@@H]1COC(=O)N1
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)C1=O
Product: CC(=O)N1CCN(c2cc(N3C(=O)OC[C@H]3C)ccc2C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)C1=O
Yield: 15.4 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using 1-acetyl-3-{5-chloro-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (344 mg) described in Preparation Example 196 and (R)-4-methyloxazolidin-2-one (61.8 mg) described in Preparation Example 25, the title compound (51.3 mg) was obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Br.[C:22]([NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][NH:31][CH2:30]2)(=[O:24])[CH3:23].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:22]([NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][N:31]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=1[F:16])[CH2:30]2)(=[O:24])[CH3:23]
Reactant: CC(=O)NCc1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Br
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)NCc1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 34 %

Procedure:
283 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 325 mg of 5-acetamidomethylisoindoline hydrobromide, 536 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 154 mg of 7-(5-acetamidomethyl-2-isoindolinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 1H-NMR (CDCl3) δ: 8.74 (1H, s, C2 --H), 7.89 (1H, d, J=14Hz, C5 --H), 7.26-7.30 (3H, brs, ARM-H), 5.15 (4H, brs, 2 x --CH2N--), 4.47 (2H, d, J=6Hz, CH2NH2), 4.00 (1H, m, ##STR310## 2.06 (3H, s, --COCH3), 1.17-1.31 (4H, m, ##STR311##
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].CC(C)([O-])C.[K+].[F:11][CH:12]([F:25])[N:13]([CH3:24])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1Cl)(=[O:16])=[O:15]>CN(C=O)C>[F:11][CH:12]([F:25])[N:13]([CH3:24])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:4][CH2:1][CH2:2][CH3:3])(=[O:16])=[O:15]
Reactant: CCCS
Reactant: CN(C(F)F)S(=O)(=O)c1ccccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1ccccc1S(=O)(=O)N(C)C(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 14.62 ml of n-propylmercaptan, 16.3 g of potassium t-butoxide and 400 ml of DMF at 0° C. was added 27.45 g (0.1076 mole) of N-difluoromethyl-N-methyl-2-chlorobenzenesulfonamide in 100 ml of DMF. The reaction mixture was stirred at room temperature for 2 days and then at 60° C. for 4 hours. The mixture was then concentrated and the residue was partitioned between 1N HCl solution and methylene chloride. The organic layer was separated, dried over MgSO4, and concentrated. The residue was chromatographed on silica gel (Hexane/chloroform 3:2) to yield 24.63 g of N-difluoromethyl-N-methyl-2-(n-propylthio)benzenesulfonamide as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:25]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)[CH:6]=[CH:5]2.C(O)C.[Cl-].[NH4+].O>[Fe]>[NH2:25][C:3]1[C:2]([CH3:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]([C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)[C:8]2=[O:12]
Reactant: Cc1ccc2c(=O)n([C@H]3CCN(C(=O)OC(C)(C)C)C3)ccc2c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(=O)n([C@H]3CCN(C(=O)OC(C)(C)C)C3)ccc2c1N
Reaction time: 0.5 h

Procedure:
A round bottom flask was charged with (S)-tert-butyl 3-(6-methyl-5-nitro-1-oxoisoquinolin-2(1H)-yl)pyrrolidine-1-carboxylate (500.0 mg, 0.001339 mol), ethanol (5 mL, 0.08 mol) and ammonium chloride (716.3 mg, 0.01339 mol) in water (3 mL, 0.2 mol) was added at 85° C. Iron (299 mg, 0.00536 mol) was added in portions and was stirred at that temperature for 30 minutes, poured onto methylene chloride (50 mL) and extracted. The solvent was removed under reduced pressure to afford the pure product as light yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10]Br)[C:4]=1[O:12][CH3:13].[CH3:14][N:15]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][N:18]([CH3:24])[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH3:24][N:18]1[CH2:17][CH2:16][N:15]([CH3:14])[CH2:23][CH2:22][N:21]([CH2:2][C:3]2[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][N:21]3[CH2:22][CH2:23][N:15]([CH3:14])[CH2:16][CH2:17][N:18]([CH3:24])[CH2:19][CH2:20]3)[C:4]=2[O:12][CH3:13])[CH2:20][CH2:19]1
Reactant: COc1c(CBr)cc(C)cc1CBr
Reactant: CN1CCNCCN(C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1c(CN2CCN(C)CCN(C)CC2)cc(C)cc1CN1CCN(C)CCN(C)CC1

Procedure:
0.31 g (1 mmol) of 2,6-bis bromomethyl-4-methylanisole are added over the course of 30 min to a solution of 0.31 g (2 mmol) of 1,4-dimethyl-1,4,7-triazacyclononane, 0.14 g of K2CO3 (1 mmol) in 10 ml of toluene, and the reaction mixture is refluxed under a protective gas for 2 days.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[OH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=3[CH3:27])[C:21](O)=[O:22])=[CH:15][CH:16]=2)[CH:11]=[N:10][N:9]=1>>[OH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=3[CH3:27])[C:21]([O:5][CH2:1][CH3:2])=[O:22])=[CH:15][CH:16]=2)[CH:11]=[N:10][N:9]=1
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(O)nncc2c1
Reactant: O=C(Cl)C(=O)Cl
Product: CCOC(=O)c1ccc(C)c(-c2ccc3c(O)nncc3c2)c1
Temperature: 0 °C
Yield: 99.1 %

Procedure:
To a 250 mL dry flask containing anhydrous ethanol (50 mL) stirred at 0° C. was added dropwise oxalyl chloride (54 mmol). After 5 minutes 3-(1-hydroxyphthalazin-6-yl)-4-methylbenzoic acid (18 mmol) was added in one portion, the suspension was warmed up to reflux and stirred for 3 h. The solvent was evaporated and the residue was vacuum dried at RT for about 2 h to give ethyl 3-(1-hydroxyphthalazin-6-yl)-4-methylbenzoate 5.5 g as an off white solid.
Reaction SMILES: [CH2:1](OC(OCC)OCC)C.[NH2:11][C:12]1[CH:33]=[C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)[CH:31]=[CH:30][C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[C:21]([C:23]([NH:25][CH:26]2[CH2:28][CH2:27]2)=[O:24])[CH:20]=[CH:19][C:18]=1[CH3:29])=[O:15].Cl.C(=O)(O)[O-].[Na+]>C(O)C.C(O)(=O)C>[CH:26]1([NH:25][C:23](=[O:24])[C:21]2[CH:20]=[CH:19][C:18]([CH3:29])=[C:17]([N:16]3[C:14](=[O:15])[C:13]4[C:12](=[CH:33][C:32]([N:34]5[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]5)=[CH:31][CH:30]=4)[N:11]=[CH:1]3)[CH:22]=2)[CH2:28][CH2:27]1
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(N2CCN(C)CC2)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2cc(N3CCN(C)CC3)ccc2c1=O
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Triethylorthoformate (0.18 ml) was added to a stirred mixture of 2-amino-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-(4-methylpiperazin-1-yl)benzamide (0.152 g) and glacial acetic acid (0.011 ml) in ethanol (30 ml). The mixture was heated to 90° C. and stirred for 16 hours. To the mixture was added 1N HCl (1 ml) and heated to 90° C. for 2 hours. The reaction mixture was made basic with sodium bicarbonate and evaporated, dissolved in ethyl acetate and washed with water. The organic phase was dried (magnesium sulphate) and evaporated to give the title compound (0.098 g); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.70 (m, 2H), 2.13 (s, 3H), 2.31 (s, 3H), 2.56 (m, 4H), 2.86 (m, 1H), 3.44 (m, 4H), 7.05 (d, 1H), 7.27 (m, 1H), 7.51 (d, 1H), 7.80 (d, 1H), 7.89 (m, 1H), 7.99 (d, 1H), 8.16 (s, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 418.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[SH:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].C(OCC)(=O)C>CN(C)C=O>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[S:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:5]
Reactant: COC(=O)CCCS
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCCSc1ccccc1C=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 95 %

Procedure:
Under an argon atmosphere, 2-fluorobenzaldehyde (3 g) was dissolved in 9 ml of dimethylformamide and potassium carbonate (5.01 g) was added. Methyl 4-mercaptobutyrate (4.5 ml) was added at room temperature and-was stirred at room temperature for 14 hours. After the addition of 50 ml of ethyl acetate, the mixture was washed with 30 ml of water twice, 3 ml of a 1N hydrochloric acid, and 30 ml of water three times. After drying with anhydrous sodium sulfate, the mixture was concentrated. The concentrated matter was subjected to silica gel chromatography (hexane/ethyl acetate=6/1) purification. The resulting effective fractions were concentrated to yield methyl 4-(2-formylphenylthio)butyrate (5.45 g, Yield 95%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][C:17]=1[O:25][CH3:26])(=[O:14])[CH3:13]>N1C=CC=CC=1.O>[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][O:24][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])=[CH:18][C:17]=1[O:25][CH3:26])(=[O:14])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(CCO)ccc1OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(CCOS(=O)(=O)c2ccc(C)cc2)ccc1OC(C)=O
Reaction time: 72 h

Procedure:
p-Toluenesulfonyl chloride (2.14 mL, 11.2 mmol) was added to a stirred solution of 4-(2-hydroxyethyl)-2-methoxyphenyl acetate (1.18 g, 5.61 mmol) in dry pyridine (20 mL) at 0° C. under N2. The reaction was stored at 4° C. for 3 days. The reaction was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to afford 2-methoxy-4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)phenyl acetate, as an oil. Product was a 6:4 mixture of desired product and starting material but carried forward regardless. LCMS calc.=387.1; found=386.8 (M+Na)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[S:3][C:4]3[CH2:5][C:6]4[C:12]([C:13]5[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=5)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:7]=4[C:8]=3[CH:9]=2)=[CH:32][CH:31]=1
Reactant: CC1(C)OB(c2ccc(F)cc2)OC1(C)C
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(F)cc4)cc2-3)cc1
Temperature: 100 °C
Yield: 66 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.87 g, 1.8 mmol), 2-(4-Fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.4 g, 2.7 mmol), Na2CO3 (2 M, 4.3 ml), and Pd(PPh3)2Cl2 (170 mg, 0.14 mmol) in toluene/ethanol (1:1, 10 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 2-(4-Fluoro-phenyl)-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as brown solid in 66% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][NH:10][C:5]2=[C:4]([CH3:11])[CH:3]=1.[H-].[Na+].I[CH2:15][CH2:16][CH3:17].O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][N:10]([CH2:15][CH2:16][CH3:17])[C:5]2=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Cl)nc2cc[nH]c12
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1ccc2nc(Cl)cc(C)c21

Procedure:
A solution of 5-chloro-7-methyl-1H-pyrrolo[3,2-b]pyridine (5 mmol) in dry DMF (10 mL) cooling on an ice bath was treated with NaH (60 mmol) under N2. After stirring at room temperature for 45 minutes iodopropane (10 mmol) was added. The mixture was allowed to react for further 3 hrs. Upon cooling on an ice bath it was treated with H2O (3 mL). The mixture was then extracted with diethyl ether (4×50 mL). The ether layers were combined, washed with brine, dried on MgSO4 and filtered. The solvent was evaporated to give 5-chloro-7-methyl-1-propyl-1H-pyrrolo[3,2-b]pyridine as orange oil. 1H-NMR (DMSO-d6) δ: 0.85 (t, 3H, J=7.6 Hz, CH3), 1.75 (m, 2H, CH2), 4.28 (t, 2H, J=7.6 Hz, CH2), 6.48 (d, 1H, J=3.2 Hz, Ar—H), 6.97 (s, 1H, Ar—H), 7.66 (d, 1H, J=3.6 Hz, Ar—H). MS (ESI+) m/z 209.0648 (M+H)+.
Reaction SMILES: O[Li].O.[OH:4][C:5]1([C:16]([O:18]C)=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[O:8][CH2:7][CH2:6]1>O.C1COCC1>[OH:4][C:5]1([C:16]([OH:18])=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[O:8][CH2:7][CH2:6]1
Reactant: COC(=O)C1(O)CCOc2ccc(C)cc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C(O)(C(=O)O)CCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of LiOH.H2O (0.78 g; 18.6 mmol) in water (15 mL) was added to a solution of 4-hydroxy-6-methylchroman-4-yl-carboxylic acid, methyl ester (2.2 g; 9.3 mmol; from step (i) above) in THF (10 mL). The reaction mixture was stirred at room temperature overnight, THF was evaporated and the water phase was washed with ether. The resultant solution was acidified with HCl (2M) and extracted with ether. The organic layer was dried (Na2SO4) and evaporated, yielding the sub-title compound. Yield: 1.21 mg (62%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([C:25]#[C:26][CH2:27][CH2:28][CH2:29]O)[CH:22]=[CH:23][CH:24]=1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:29][CH2:28][CH2:27][C:26]#[C:25][C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:31])[F:32])[CH:20]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: OCCCC#Cc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCCCC#Cc3cccc(C(F)(F)F)c3)cc21

Procedure:
In analogy to the procedure described for example 1 d], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 1 c]) was reacted with 5-(3-trifluoromethyl-phenyl)-pent-4-yn-1-ol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give the title compound as yellow oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][CH:9]([NH2:11])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)[O:19][CH2:18][CH2:17][CH:16]2[C:33]([O:35][CH2:36][CH3:37])=[O:34].Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.CCOC(C)=O>[Cl:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](=[O:29])[NH:11][CH:9]3[CH2:8][CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:10]3)=[CH:26][CH:25]=1)[O:19][CH2:18][CH2:17][CH:16]2[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NC1CC(c2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CC(c5ccccc5)C4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.6 %

Procedure:
To a solution of 3-phenylcyclobutanamine (0.101 g, 0.686 mmol) in DMF (2 ml) was added 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.129 g, 0.343 mmol), N,N-dimethylpyridin-4-amine (0.00838 g, 0.0686 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.0789 g, 0.412 mmol), and the reaction was stirred for 16 hours at ambient temperature. The reaction was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was on a Biotage SP1 system eluting with a 5-70% EtOAc in hexanes linear gradient to yield 86 mg of the title compound (49.5% yield).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[CH3:8].CN([CH:14]=[O:15])C.C[O-].[Na+]>O>[Br:1][C:2]1[C:3]([O:15][CH3:14])=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[CH3:8]
Reactant: CN(C)C=O
Reactant: Cc1c(F)cnc(Cl)c1Br
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1ncc(F)c(C)c1Br
Temperature: 80 °C
Reaction time: 2 h

Procedure:
3-bromo-2-chloro-5-fluoro-4-methylpyridine (340 mg) was added to DMF (1.8 mL). Sodium methoxide (28% solution in methanol, 5.4 mL) was added to the solution, and the mixture was stirred at 80° C. for two hours. Water was added to the reaction mixture. The precipitated solid was collected by filtration to give the title compound (240 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]=O)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:14][NH:15][CH3:16].O1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:15]([CH3:16])[CH3:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(C=O)c1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1cc(Br)cc(CN(C)C)c1
Reaction time: 0.25 h

Procedure:
To a solution of methyl 3-bromo-5-formylbenzoate (1.8 g, 7.4 mmol, prepared as described in WO 2003048111 from dimethyl 5-bromoisophthalate, Alfa Aesar) in methylene chloride (20 mL) was added a solution of 2.0 M dimethylamine in tetrahydrofuran (7.4 mL, 15 mmol). This mixture was stirred for 15 minutes, followed by the addition of sodium triacetoxyborohydride (4.7 g, 22 mmol). The resulting mixture was stirred overnight. Saturated sodium bicarbonate solution was added and the product was extracted with ethyl acetate. The combined organic extracts were washed twice with water, once with brine, dried over sodium sulfate, filtered and concentrated to afford a light yellow oil. Yield: 1.87 g (93%); LC-MS: 272.0, 274.0 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 8.06 (dd, 1H), 7.89 (dd, 1H), 7.69 (dd, 1H), 3.91 (s, 3H), 3.42 (s, 2H), 2.24 (s, 6H).
Reaction SMILES: [Cl-].[CH:2]1([CH2:5][NH2+:6][CH2:7][CH2:8]Cl)[CH2:4][CH2:3]1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N:18]=[C:19]=[S:20]>>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N:18]=[C:19]1[N:6]([CH2:5][CH:2]2[CH2:3][CH2:4]2)[CH2:7][CH2:8][S:20]1
Reactant: ClCC[NH2+]CC1CC1
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Agent: [Cl-]
Product: Clc1ccc(N=C2SCCN2CC2CC2)c(Cl)c1

Procedure:
2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopropylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,4-dichlorophenyl isothiocyanate to give 2-(2,4-dichlorophenylimino)-3-(cyclopropylmethyl)-1,3-thiazolidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2.[Li]CCCC.CON(C)[C:20](=[O:24])[CH2:21][CH2:22][CH3:23]>C1COCC1>[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:20](=[O:24])[CH2:21][CH2:22][CH3:23])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Cn1ccc2cc(Br)ccc21
Reactant: CCCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC(=O)c1ccc2c(ccn2C)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 57.4 %

Procedure:
To a solution of 5-bromo-1-methyl-1H-indole (9.8 g, 46.7 mmol) in THF (40 mL) was added n-BuLi (2.5M in hexanes, 22.3 mL, 55.8 mmol, 1.2 eq) at −78° C. dropwise over 15 min. The mixture was stirred for 30 min at −78° C. before a solution of N-methoxy-N-methylbutyramide (7.35 g, 56.0 mmol, 1.2 eq) in THF (10 mL) was added. After stirred at −78° C. for 10 min, the reaction was quenched with saturated aqueous NH4Cl. The resulting mixture was extracted by ether (3×30 mL) and combined organic layers were dried over Na2SO4. The crude product was purified by flash chromatography (0-10% EtOAc in hexanes) to give the title compound (5.40 g, 26.8 mmol, 57%) as a white solid.