Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[C:17]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[C:17]1(=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCCCCC1
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of zinc powder (15.0 g, 0.23 mol) in THF (300 mL) was slowly added TiCl4 (12.5 mL, 0.115 mol) via a syringe at room temperature under a nitrogen atmosphere. The reaction mixture was heated at reflux for 1 h. A solution of bis(4-hydroxyphenyl)methanone (4.9 g, 0.023 mol) and cycloheptanone (7.74 g, 0.07 mol) in THF (100 mL) was added to the reaction mixture. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for an additional 2 h. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into a 10% aqueous K2CO3 (1 L). The reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc. The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous phase was further extracted with EtOAc (4×250 mL). The combined organic phase was washed with brine (2×100 mL), dried (Na2SO4), filtered, and then concentrated under reduced pressure to give the crude product as a gold-yellow oil. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 50:50) as an eluent to afford 6.75 g (99%) of the title compound 189 as a white solid. 1H NMR (DMSO-d6): δ 9.21 (s, 2H), 6.84 (d, J=6.3 Hz, 4H), 6.63 (d, J=6.3 Hz, 4H), 2.19 (br s, 4H), 1.48 (br s, 8H). LCMS (ESI): m/z 294 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:7][CH2:8][C:9]([NH2:11])=O)[NH:5][CH:6]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]([CH2:7][CH2:8][C:9]#[N:11])[NH:5][CH:6]=1
Reactant: Cc1c[nH]c(CCC(N)=O)n1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Product: Cc1c[nH]c(CCC#N)n1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
Into a 250-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, were placed a solution of 3-(4-methyl-1H-imidazol-2-yl)propanamide (compound 232.3, 2 g, 13.06 mmol) in toluene (100 mL) and P2O5 (2 g, 14.08 mmol). The reaction mixture was stirred for 12 h at 120° C., then quenched with 100 mL of water. The aqueous phase was extracted with 2×200 mL of ethyl acetate and the combined organic layers were washed with 2×100 mL of sodium carbonate (sat.), dried over sodium sulfate and concentrated under reduced pressure. This resulted in 1 g (57%) of 3-(4-methyl-1H-imidazol-2-yl)propanenitrile as light yellow oil
Reaction SMILES: Cl.[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH2:11].O.O.O.[C:15]([O-])(=[O:17])[CH3:16].[Na+].C(OC(=O)C)(=O)C>>[C:15]([NH:11][CH:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2]1)(=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)NC1Cc2ccccc2C1

Procedure:
25 g. of 2-indanamine hydrochloride (0.15 mole), 20 g. of sodium acetate trihydrate (0.14 mole), and 40 g. of acetic anhydride (0.4 mole) were stirred at 25° C. for sixteen hours. The mixture was evaporated and the residue was partitioned between chloroform and water. The chloroform extracts were pooled, washed with 10% hydrochloric acid and then with 5% aqueous sodium carbonate, dried and evaporated to yield N-acetyl-2-indanamine.
Reaction SMILES: C(O)CCC#C.[Cl:7][C:8]1[CH:9]=[C:10]([C:15]#[C:16][CH2:17][CH2:18][CH:19]=[O:20])[CH:11]=[CH:12][C:13]=1[F:14]>>[Cl:7][C:8]1[CH:9]=[C:10]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: O=CCCC#Cc1ccc(F)c(Cl)c1
Agent: C#CCCCO
Product: OCCCC#Cc1ccc(F)c(Cl)c1

Procedure:
5-(3'-chloro-4'-fluorophenyl)-4-pentyn-1-ol was prepared from 4-pentyn-1-ol and 3'-chloro-4'-fluoro-iodobenzene as in Example 15 and converted into 5-(3'-chloro-4'-fluorophenyl)-4-pentyn-1-al as in Example 9.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl.C(=O)(O)[O-].[Na+]>CO.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-c2cccc([N+](=O)[O-])c2)cc1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: COC(=O)c1ccc(-c2cccc(N)c2)cc1
Yield: 72.1 %

Procedure:
A mixture of methyl 4-(3-nitrophenyl)benzoate (8.37 g), iron powder (7.5 g) and hydrochloric acid (35%, 22 ml) in methanol (60 ml) was stirred under reflux for 3 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give methyl 4-(3-aminophenyl)benzoate (5.33 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[CH:12]1([C:15]2[CH:16]=[C:17]([CH3:27])[C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:18]3[C:17]([CH3:27])=[CH:16][C:15]([CH:12]4[CH2:13][CH2:14]4)=[CH:20][N:19]=3)[CH2:22][CH2:23]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: Cc1cc(Br)ccc1C(=O)O
Product: Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Yield: 54 %

Procedure:
Using 4-bromo-2-methylbenzoic acid (1.00 g) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (1.52 g) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (1.04 g) was obtained.
Reaction SMILES: C(O)=O.C(O[C:8](=[O:10])[CH3:9])(=O)C.[O:11]=[C:12]1C[NH:16][CH2:15][CH2:14][NH:13]1>C(Cl)Cl>[CH:12]([N:13]1[CH2:14][CH2:15][NH:16][C:8](=[O:10])[CH2:9]1)=[O:11]
Reactant: O=C1CNCCN1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O=CO
Product: O=CN1CCNC(=O)C1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
To 80 ml of formic acid was added 28 ml of acetic anhydride at room temperature, and the mixture was stirred at 60° C. for 20 minutes. After stirring at room temperature for further 15 minutes, the reaction mixture was added dropwise to a solution of 4.2 g of 2-oxopiperazine in 400 ml of methylene chloride at 0° C. over a period of 1.25 hours, and the resulting mixture was stirred at 0° C. for further 30 minutes. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was recrystallized from acetone/hexane to give 3.0 g (56%) of 1-formyl-3-oxopiperazine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].P(Cl)(Cl)(Cl)(Cl)[Cl:12].C1(O)C=CC=CC=1>C(OCC)C.CO.O>[Cl:12][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[F:1]
Reactant: O=C(O)c1ccccc1F
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: CCOCC
Solvent: Oc1ccccc1
Product: O=C(Cl)c1ccccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 130.7 %

Procedure:
To a stirred suspension of 95.4 g of 2-fluorobenzoic acid, 2-(4-(trifluoromethyl)phenylhydrazide, in 400 ml of anhydrous diethyl ether was added, portionwise, 80.0 g of phosphorous pentachloride. Upon completion of the addition, the reaction mixture was refluxed for 1 hour and then stirred at room temperature for 16 hours. In the following order, a solution of 81.3 g of phenol in 80 ml of diethyl ether, 385 ml of methanol and sufficient water to reach the solution cloud point, were added, dropwise, to the reaction mixture. Upon standing, the reaction mixture separated into two layers. The top layer (aqueous) was extracted with diethyl ether and the extract added to the bottom layer (organic). The combined organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated to an oil. The oil was purified on a Water's Model 500 High Pressure Liquid Chromatograph using two silica gel columns and 5% ethyl acetate-hexane as the eluent. Concentration of the appropriate fractions gave 79.6 g (78.5%) of α-chloro-2-fluorobenzaldehyde, [4-(trifluoromethyl)phenyl]-hydrazone. Subsequent recrystallization from hexane gave an analytical sample, mp 48°-50°.
Reaction SMILES: [F:1][CH2:2][O:3][N:4]=[C:5]([C:10]1[N:14]=[C:13]([NH2:15])[S:12][N:11]=1)[C:6]([O:8][CH3:9])=[O:7].[CH:16](O)=[O:17].C(OC(=O)C)(=O)C>>[F:1][CH2:2][O:3][N:4]=[C:5]([C:10]1[N:14]=[C:13]([NH:15][CH:16]=[O:17])[S:12][N:11]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(=NOCF)c1nsc(N)n1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(=NOCF)c1nsc(NC=O)n1
Yield: 75.6 %

Procedure:
To a suspension of methyl 2-fluoromethoxyimino-2-(5-amino-1,2,4-thiadiazole-3-yl)-acetate (anti-isomer) (1.17 g, 5 mmol) in formic acid (1.38 g, 30 mmol), acetic anhydride (1.12 g, 10 mmol) was added. The mixture was treated in the same procedure as described in Example 9 to give methyl 2-fluoromethoxyimino-2-(5-formamido-1,2,4-thiadiazole-3-yl)-acetate (syn-isomer) (991 mg, yield: 73.8%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35](O)=[O:36])[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:44][C@@H:43]([C:45]2[N:46]=[CH:47][C:48]([NH2:51])=[N:49][CH:50]=2)[CH2:42][O:41]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:44][C@@H:43]([C:45]1[N:46]=[CH:47][C:48]([NH:51][C:35]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:38])[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17]2)=[O:36])=[N:49][CH:50]=1)[CH2:42][OH:41]
Reactant: CC1(C)OC[C@H](c2cnc(N)cn2)O1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)CC1NC(C(=O)Nc2cnc([C@H](O)CO)cn2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 11.6 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (0.1 g, 0.2 mmol) was reacted with 5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-ylamine (46 mg, 0.24 mmol), T3P (Aldrich) (0.32 mL, 0.53 mmol) and iPr2NEt (0.11 mL, 0.64 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-amide as a white solid (14 mg, 11%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9](C)[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]CC)=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:23].[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[NH:9][CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:23]
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c-2ccc(F)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ncn2c1CNC(=O)c1c-2ccc(F)c1Cl

Procedure:
14.55 g (43 mmol) of ethyl 7-chloro-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate was heated to boiling under reflux for 15 minutes with 1.90 g (45.7 mmol) of sodium hydroxide in 80 ml of ethanol and 30 ml of water. The reaction mixture was then cooled and treated with 10.4 ml of 4N hydrochloric acid. By suction filtering the suspension obtained and drying the product there was obtained 7-chloro-8-fluoro-5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid of decomposition point 260°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:24][CH:25]([NH2:30])[C:26]([F:29])([F:28])[F:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][C@@H:25]([CH3:24])[C:26]([F:29])([F:28])[F:27])=[O:21])=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Reactant: CC(N)C(F)(F)F
Product: C[C@H](NC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1)C(F)(F)F
Yield: 98 %

Procedure:
As described for example 346b, 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (150 mg, 0.45 mmol) was converted, using L-2,2,2-trifluoro-1-(methyl)ethylamine instead of ethanolamine, to the title compound (190 mg, 98%) which was obtained as a white solid. MS: m/e=424.0 [M−H]−.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([CH:14]([CH2:27][CH3:28])[CH2:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=1)[CH3:13].[CH3:29][O:30][C:31]1[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[CH:42][C:32]=1[CH2:33][N:34]1[C:38](=[O:39])[CH2:37][NH:36][S:35]1(=[O:41])=[O:40]>C(Cl)Cl>[CH2:12]([CH:14]([CH2:27][CH3:28])[CH2:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:36]2[CH2:37][C:38](=[O:39])[N:34]([CH2:33][C:32]3[CH:42]=[CH:43][C:44]([O:46][CH3:47])=[CH:45][C:31]=3[O:30][CH3:29])[S:35]2(=[O:40])=[O:41])=[CH:20][CH:19]=1)[CH3:13]
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)c(OC)c1
Reactant: CCC(CC)COC(=O)c1ccc(CBr)cc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(CC)COC(=O)c1ccc(CN2CC(=O)N(Cc3ccc(OC)cc3OC)S2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DBU (127 mg, 0.836 mmol) is added slowly to a suspension of the title B compound, 4-bromomethyl-benzoic acid 2-ethyl-butyl ester (250 mg, 0.836 mmol) and the title B compound in Example 9, 2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (240 mg, 0.836 mmol) in 10 mL of CH2Cl2 at RT. The resulting solution is stirred at RT overnight. The solvent is evaporated under reduced pressure and the residue is chromatographed on silica gel with EtOAc/hexane (gradient 60-40) to afford 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo1,2,5-thiadiazolidin-2-ylmethyl]-benzoic acid 2-ethyl-butyl ester as a white solid.
Reaction SMILES: [P].[C:2]1([C:4](=[CH:6][CH:7]=[CH:8][CH:9]=1)[OH:5])[OH:3].[CH3:10]O>>[C:4]1([O:5][CH3:10])[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:3]
Reactant: CO
Reactant: Oc1ccccc1O
Agent: [P]
Product: COc1ccccc1O
Temperature: 230 °C

Procedure:
The mixed catechol-methyl alcohol vapor delivered from the evaporator was super heated to a temperature of 230° C. by a heat exchanger using a heating medium, mixed with a mixed gas separately prepared from a boron compound as a component of an etherification (dehydration reaction) catalyst and methyl alcohol, and then fed, as a material vapor, into a gas phase reactor packed with a phosphorus-containing etherification catalyst (as disclosed in Japanese Unexamined Patent Publication No. 4-341,345, Example 1). In the reactor, catechol catalytically reacted with methyl alcohol at a reaction temperature of 270° C. under a reaction pressure of 0.35 kg/cm2G, to produce guaiacol. The resultant guaiacol-containing gas was delivered from the reactor, and cooled and condensed by a cooler. The condensed liquid was collected from the cooler and stored in a storage tank.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[S:7]([C:10]1[CH:19]=[C:18]2[C:13]([C:14](=O)[NH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].O=P(Cl)(Cl)[Cl:34]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:34][C:14]1[C:13]2[C:18](=[CH:19][C:10]([S:7]([N:6]([CH2:5][C:4]3[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:3]=3[O:2][CH3:1])[C:21]3[S:22][CH:23]=[CH:24][N:25]=3)(=[O:9])=[O:8])=[CH:11][CH:12]=2)[N:17]=[CH:16][N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(=O)[nH]cnc3c2)c(OC)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncnc3c2)c(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-(2,4-dimethoxybenzyl)-4-oxo-N-(thiazol-2-yl)-3,4-dihydroquinazoline-7-sulfonamide (0.990 g, 2.159 mmol) was dissolved in toluene (10.80 ml) and POCl3 (0.403 ml, 4.32 mmol) was added. The reaction was stirred for 90 minutes at room temperature, then heated to 90° C. and stirred for four hours. The reaction was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated to afford a brown oily solid. The solid was triturated in heptane, stirred for 30 minutes, and filtered. The resulting material was vacuum dried to afford crude 4-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide as a free flowing tan solid. (ESI) 499.1 (M+Na)+.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[H-].[Na+].Cl.Cl[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>CN(C=O)C>[O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCNC1=O
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCCN(Cc2cccnc2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
To a stirred solution of (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (230 mg, 1.01 mmol) in DMF (1 mL) was added sodium hydride (129 mg, 3.22 mmol) at rt under argon. The reaction mixture was stirred at rt for 10 min followed by the addition of 3-(chloromethyl)pyridine hydrochloride (197 mg, 1.54 mmol) at rt. The reaction was allowed to stir at rt for an additional 30 min. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with water, saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-80% EtOAc/Hex to give (S)-tert-butyl 2-oxo-1-(pyridin-3-ylmethyl)azepan-3-ylcarbamate (155 mg, 0.485 mmol, 48.2% yield) as colorless oil. Anal. Calcd. for C17H25N3O3 m/z 319.4. found: 320.2 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:32][CH2:31][C:19]3([N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21][CH2:20]3)[CH2:18]2)=[CH:13][C:12]=1[O:33][CH:34]([CH3:36])[CH3:35])([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:32][CH2:31][C:19]3([NH:23][CH2:22][CH2:21][CH2:20]3)[CH2:18]2)=[CH:13][C:12]=1[O:33][CH:34]([CH3:36])[CH3:35])([O-:10])=[O:9]
Reactant: CC(C)Oc1cc(N2CCC3(CCCN3C(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1cc(N2CCC3(CCCN3)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.8 %

Procedure:
0.33 ml of trifluoroacetic acid is added to a solution of 300 mg of 2-methylpropan-2-yl 7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane-1-carboxylate in 30 ml of dichloromethane. The mixture is stirred at ambient temperature for 15 hours and then 3 ml of trifluoroacetic acid are again added. After stirring for 15 hours, the reaction mixture is run into 50 ml of a saturated potassium carbonate solution. The aqueous phase is extracted three times with 50 ml of dichloromethane. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered and then concentrated to dryness under reduced pressure, so as to give a yellow oil. The residue is purified by chromatography on silica gel, elution being carried out with dichloromethane/methanol (100/0 to 95/5), so as to obtain 221 mg of 7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane in the form of a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][N:11]3[CH:18]=2)=[CH:4][C:3]=1[I:19].C(=O)([O-])[O-].[K+].[K+].[F:26][CH2:27][CH2:28]OS(C1C=CC(C)=CC=1)(=O)=O.[Cl-].[NH4+]>>[F:26][CH2:27][CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][N:11]3[CH:18]=2)=[CH:4][C:3]=1[I:19]
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: COc1ccc2nc(-c3ccc(O)c(I)c3)cn2c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Product: COc1ccc2nc(-c3ccc(OCCF)c(I)c3)cn2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
366 mg (corresponding to 1.00 mmol) of 2-(4′-hydroxy-3′-iodophenyl)-6-methoxyimidazo[1,2-a]pyridine that was sufficiently dried to remove moisture was dissolved in 10.0 mL of N,N-dimethylformamide, and 415 mg (corresponding to 3.00 mmol) of potassium carbonate was added thereto. The mixture was supplemented with 327 mg (corresponding to 1.50 mmol) of 1-fluoro-2-paratoluenesulfonyloxyethane, and then the solution was stirred at 90° C. for 2 hours. After the completion of the reaction, a saturated aqueous ammonium chloride solution was added thereto, and extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=½), to obtain 381 mg (corresponding to 0.924 mmol) of 2-[4′-(2″-fluoroethoxy)-3′-iodophenyl]-6-methoxyimidazo[1,2-a]pyridine (FIG. 5, Step 2).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4](S(C)=O)[N:3]=1.[OH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:3]=1
Reactant: OCc1ccccn1
Reactant: CS(=O)c1nc(N)c(C#N)c(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(N)nc(OCc2ccccn2)c(C#N)c1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyridine-3,5-dicarbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. EI-MS m/e (%): 317 (M+, 66), 92 (100), 65 (55).