Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[N:13]=[C:12]2[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:11]2=[CH:10][C:9]=1[CH:19]=[O:20].[CH2:21]([NH:23][CH2:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][O:26]1)[CH3:22].O>CN(C)C=O.C(OCC)(=O)C>[CH2:21]([N:23]([CH2:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][O:26]1)[C:8]1[N:13]=[C:12]2[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:11]2=[CH:10][C:9]=1[CH:19]=[O:20])[CH3:22]
Reactant: CCNC[C@@H]1CCCO1
Reactant: Cc1nn(C)c2nc(Cl)c(C=O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(C[C@@H]1CCCO1)c1nc2c(cc1C=O)c(C)nn2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
Potassium carbonate (0.42 g, 3 mmol) was added to a solution of 6-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (0.46 g, 2.2 mmol) and (S)-(+)-ethyl-(tetrahydro-furan-2-ylmethyl)-amine (4.8 mmol) in anhydrous dimethyl formamide (6 mL) under nitrogen. After stirring for 0.5 h at RT, the reaction mixture was heated for 20 h at 80-95° C. Thereafter, the reaction was cooled to RT, water (30 mL) and ethyl acetate (30 mL) were added, and the organic layer was separated from the aqueous mixture. The organic extract was washed with brine, dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by chromatography using silica gel (200-400 mesh) to afford the title compound as a pale yellow liquid (0.35 g, yield: 53%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Cl:17]N1C(=O)CCC1=O>CCCCCC.C1COCC1.CCOCC>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([Cl:17])=[CH:8][C:6]=2[N:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Clc1nc(N2CCOCC2)c2sc(Cl)cc2n1
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 50 %

Procedure:
n-Butylithium (1.6 mL, 3.914 mmol) in 2.5 M hexane solution was added to a mixture of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine 4 (500 mg, 1.957 mmol) in 10 mL of THF at −78° C. The reaction mixture was allowed to warm to −40° C. and stirred for 40 min. A solution of N-chlorosuccinimide (523 mg, 3.914 mmol) in 8 mL of THF was added dropwise. After the addition was completed. The reaction mixture was brought to room temperature and stirred for 2 h. The reaction was monitored by LC/MS. The mixture was diluted with ether and extracted with 1N HCl (2×60 mL). The aqueous layer was then basified and extracted with ethyl acetate (2×100 mL). The organic layer was washed with H2O (60 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by ISCO Combiflash (5˜50% ethyl acetate/hexane) to afford 2,6-dichloro-4-morpholinothieno[3,2-d]pyrimidine (284 mg, 50%).
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[OH:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]1.O>C(Cl)Cl>[N:3]1([C:1]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]2)=[O:2])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)N1CCN(CCO)CC1
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCN(CCOC(=O)n2ccnc2)CC1
Yield: 95.8 %

Procedure:
A solution of 1,1′-carbonyldiimidazole (5 g, 31 mmol) in DCM (200 mL) was treated with a solution of 1-[4-(2-hydroxyethyl)-1-piperazinyl]-1-ethanone (from step (i) above; 5 g, 29 mmol) in DCM (50 mL). The reaction mixture was stirred at rt overnight before water was added. The layers were separated, and the organic layer was washed with water, dried lo and concentrated in vacuo to yield 7.4 g (96%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][CH:3]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=c1[nH]cc(Cl)c2ccccc12
Product: O=c1[nH]cc(Cl)c2ccc(S(=O)(=O)Cl)cc12
Temperature: 100 °C
Yield: 58.6 %

Procedure:
LRMS 180, 182 (MH+), 359, 361, 363 (M2H+). ##STR108## 4-Chloro-1-(2H)-isoquinolone (20.62 g, 115 mmol) was added portionwise to stirred chlorosulphonic acid (61 mL, 918 mmol) at 0° C. The mixture was heated at 100° C. for 3.5 d and then cooled to room temperature. The reaction mixture was added in small portions onto ice-water [CAUTION] and the resulting precipitate was collected by filtration. The solid was washed with water, triturated with MeCN and then dried in vacuo to give 4-chloro-1-oxo-1,2-dihydro-7-isoquinolinesulphonyl chloride (18.75 g, 67.4 mmol) as a cream solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([CH:11]([CH3:13])[CH3:12])=[C:4]([Br:14])[C:3]=1[OH:15].CO[CH2:18][Cl:19]>C(=S)=S>[Br:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([CH2:18][Cl:19])[C:5]([CH:11]([CH3:13])[CH3:12])=[C:4]([Br:14])[C:3]=1[OH:15]
Reactant: COCCl
Reactant: CC(C)c1cc(C(C)C)c(Br)c(O)c1Br
Solvent: S=C=S
Product: CC(C)c1c(Br)c(O)c(Br)c(C(C)C)c1CCl

Procedure:
Three hundred thirty-six parts of 2,6-dibromo-3,5-diisopropylphenol [prepared as described in Canad, J. Chem., Vol. 41, p. 1653 (1963)] is allowed to react with 130 parts of chloromethyl methyl ether and 80 parts of stannic chloride in 400 parts of carbon disulfide under general conditions set forth in "Organic Reactions", Vol. 1, p. 68 and 69. The reaction mixture is poured on ice, and the organic layer is separated and dried over anhydrous calcium sulfate. The solvent is allowed to evaporate and the residue is crystallized to give a pure sample of the title compound. Chloromethylation of the following monohalo- or dihalodialkylphenols gives the corresponding chloromethyl derivatives.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[CH2:16]O)=[CH:10][CH:9]=2)[CH:2]=1.S(Cl)([Cl:20])=O>C(Cl)Cl>[ClH:20].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[CH2:16][Cl:20])=[CH:10][CH:9]=2)[CH:2]=1
Reactant: OC/C=C/c1ccc(Cc2cccnc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: ClC/C=C/c1ccc(Cc2cccnc2)cc1

Procedure:
In 5 ml of methylene chloride was dissolved 300 mg of (E)-3-[4-(pyridin-3-ylmethyl)phenyl]allyl alcohol, and 0.58 ml of thionyl chloride was dropped into the resulting solution with ice-cooling, after which the resulting mixture was subjected to reaction under reflux for 30 minutes. The solvent and the excessive thionyl chloride were removed by distillation under reduced pressure, to obtain (E)-3-[4-(pyridin-3-ylmethyl)phenyl]allyl chloride hydrochloride as the residue. This was dissolved in 3 ml of N,N-dimethylformamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:31][CH3:32])=[C:9]([S:11]([C:14]2[CH:15]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:17]=[C:18]([O:20]C(C)(C)C)[CH:19]=2)(=[O:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:31][CH3:32])=[C:9]([S:11]([C:14]2[CH:15]=[C:16]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:17]=[C:18]([OH:20])[CH:19]=2)(=[O:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(S(=O)(=O)c2cc(OC(C)(C)C)cc(-c3ccccc3)c2)c(SC)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(S(=O)(=O)c2cc(O)cc(-c3ccccc3)c2)c(SC)s1
Reaction time: 1 h
Yield: 100.4 %

Procedure:
4-(5-tert-butoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester (55 mg, 0.11 mmol) was dissolved in 1:1 TFA/DCM (10 mL) and stirring for 1 h. Removal of the solvent in vacuo yielded the title compound (48 mg, 98%), which was used without further purification.
Reaction SMILES: C([O:3][P:4]([CH2:9][C:10]1[CH:11]=[N:12][C:13]([NH:16][C:17](=[O:36])[C:18]2[CH:23]=[C:22]([O:24][CH2:25][CH2:26][C:27]3[CH:31]=[CH:30][S:29][CH:28]=3)[CH:21]=[C:20]([O:32][CH:33]([CH3:35])[CH3:34])[CH:19]=2)=[CH:14][CH:15]=1)(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.C(Cl)[Cl:43]>>[ClH:43].[CH:33]([O:32][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([O:24][CH2:25][CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[CH:21]=1)[C:17]([NH:16][C:13]1[N:12]=[CH:11][C:10]([CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[CH:15][CH:14]=1)=[O:36])([CH3:35])[CH3:34]
Reactant: CCOP(=O)(Cc1ccc(NC(=O)c2cc(OCCc3ccsc3)cc(OC(C)C)c2)nc1)OCC
Reactant: ClCCl
Agent: C[Si](C)(C)Br
Product: CC(C)Oc1cc(OCCc2ccsc2)cc(C(=O)Nc2ccc(CP(=O)(O)O)cn2)c1
Product: Cl
Temperature: -78 °C
Yield: 21.6 %

Procedure:
{6-[3-Isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoylamino]-pyridin-3-ylmethyl}-phosphonic acid diethyl ester (86.0 mg, 0.166 mmol) was dissolved in DCM (0.8 mL) and cooled to −78° C. TMSBr (0.21 mL, 1.61 mmol) was added and the reaction mixture was allowed to warm to rt over 24 hours. The reaction mixture was concentrated under reduced pressure and partitioned in diethyl ether (5 mL) and 1N aqueous sodium hydroxide (5 mL). The aqueous layer was rinsed twice with diethyl ether (5 mL), then acidified to pH=1 with concentrated hydrochloric acid and extracted with EtOAc (3×5 mL). The organic layer dried over sodium sulfate, filtered, and concentrated to give the title compound, {6-[3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoylamino]-pyridin-3-ylmethyl}-phosphonic acid hydrochloride (16.6 mg, 21.6% yield), as a pale brown foam. 1H NMR (300 MHz, DMSO-d6): δ 10.70 (s, 1H), 8.20 (s, 1H), 8.05 (d, J=6.0 Hz, 1H), 7.70 (d, J=6.0 Hz, 1H), 7.45 (d, 3.0 Hz, 1H), 7.30 (s, 1H), 7.20 (s, 1H), 7.15 (s, 1H), 7.10 (d, J=3.0 Hz, 1H), 6.65 (s, 1H), 4.70 (m, 1H), 4.25 (t, 2H), 3.10 (t, 2H), 2.95 (d, J=12.0 Hz, 2H), 1.25 (s, 6H); LCMS (m/z): 477.1 [C22H25N2O6PS+H] Anal. Calcd. for (C22H25N2O6PS+1.2 HCl): C, 50.79; H, 5.08; N, 5.38. Found: C, 50.72; H, 4.91; N, 4.80.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14](=O)[CH3:15])[CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:14]([CH3:15])[N:23]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=2)[C:10](=[O:12])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: NCc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC1CN(C(=O)OC(C)(C)C)CC(=O)N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-[(tert-butoxy)carbonyl]-N-(2-oxopropyl)glycine (0.66 g, 2.87 mmol), 4-fluorobenzylamine (0.23 g, 1.87 mmol) in dichloroethane (14 mL) was stirred at room temperature for one hour. Sodium triacetoxyborohydride (0.79 g, 3.73 mmol) was added and the reaction mixture stirred at room temperature overnight. The resultant mixture was concentrated under vacuum. The residue was dissolved in DMF (12 mL), treated with EDC (0.55 g), and stirred at room temperature overnight. The resultant mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate and dilute aqueous HCl. The organic extract was washed with brine (to pH 7), dried over anhydrous magnesium sulfate, filtered, and concentrated to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)C>O>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[O:6])=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccccc1F
Solvent: CCO
Solvent: O
Product: Nc1ccc(C(=O)c2ccccc2F)cc1
Reaction time: 1 h
Yield: 253.2 %

Procedure:
To stirred 90° C. polyphosphoric acid (200 g) was added 14.29 g (10.2 mmol) of 2-fluorobenzoic acid and aniline (9.32 g 10.0 mmol) and the bath temperature raised to 180°-190° C. and held there for 1 hour. A solution was obtained at about 140° C. The heating bath was removed and the stirred mixture (sublimate above the solution) was treated cautiously with 80 mL of water. The mixture was stirred at 140°-155° C. for 1 hour, the heating bath removed, 66 mL of 3N HCl added, the mixture poured into 1 L of water and filtered through a pad of Celite. The filtrate was basified with 15% sodium hydroxide and the solid which formed on stirring was collected. The Celite pad was washed well with methylene chloride, the methylene chloride removed and the residue was combined with the solid obtained from basification of the aqueous phase. The combined material was dissolved in refluxing ethanol (175 mL), and treated hot with 125 mL of water. The brown solid obtaing on cooling was additionally recrystallized twice from ethyl acetate-hexane. Final purification by flash column chromatography (methylene chloride) yielded the aniline as a white solid (5.45 g, 25%); mp 128°-130° C. 1H-NMR (250 MHz, d6-DMSO): 6.32 (s, 2H, NH2)6.60 (dd, 2H, J=8.6, 1.5 Hz, aromatic) 7.28-7.35 (m, 2H, aromatic) 7.40-7.60 (m, 4H, aromatic). MS (CI, CH4): 216 (M+1). Analysis for C13H10FNO: Calculated: C, 72.55; H, 4.68; N, 6.51. Found: C, 72.46; H, 4.82; N, 6.21.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:37][CH2:38][N:39]([CH3:48])[C:40]2[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.C(O)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:37][CH2:38][N:39]([CH3:48])[C:40]5[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=5)=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)c2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCN(C)c1ccc(C#N)cc1
Temperature: 75 °C
Yield: 98 %

Procedure:
To a solution of 6-(4-chlorophenyl)-3-(4-hydroxy-3-methoxyphenyl)thieno[3,2-d]pyrimidin4(3H)-one (96 mg, 0.25 mmol, the preparation of which can be found in the section detailing the preparation of Example K1) in DMF was added 2-[4-cyano(methyl)anilino]ethyl p-toluenesulfonate (165 mg, 0.50 mmol) and cesium carbonate (0.24 g, 0.75 mmol) and the mixture was stirred with heating at 75° C. for 12 h. The reaction was allowed to cool and 10 mL solution of 20% water/ethanol was added. The resulting precipitate was filtered and dried in a vacuum oven to give the title compound (133 mg, 98%). 1H NMR (DMSO-D6) δ 3.10 (3H, s), 3.76 (3H, s), 3.87 (2H, t, J=3.7 Hz), 4.21 (2H, t, J=3.7 Hz), 6.87 (1H, d, J=7.3 Hz), 7.02-7.20 (3H, m), 7.58 (4H, m), 7.99 (3H, m), 8.38 (1H, s). LCMS m/z=543 (m+H+). Calcd. for C29H23ClN4O3S×1HCl: C, 60.11; H, 4.17; N; 9.67. Found: C, 59.78; H, 4.18; N, 9.44.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH2:6][C:7]1[N:8]=[CH:9][CH:10]=[C:11]2[C:15]([CH3:16])=[C:14]([CH3:17])[NH:13][C:12]=12.[CH3:22][O:23][CH2:24][CH2:25]Br>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH2:6][C:7]1[N:8]=[CH:9][CH:10]=[C:11]2[C:15]([CH3:16])=[C:14]([CH3:17])[N:13]([CH2:25][CH2:24][O:23][CH3:22])[C:12]=12
Reactant: COCCBr
Reactant: Cc1[nH]c2c(COc3ccc(Cl)c(Cl)c3)nccc2c1C
Product: COCCn1c(C)c(C)c2ccnc(COc3ccc(Cl)c(Cl)c3)c21
Product: Cl
Yield: 70 %

Procedure:
In accordance with the same procedures as in Example 2, except for using 7-(3,4-dichlorophenoxymethyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 2 and 2-bromoethyl methyl ether, the titled compound was obtained as a white solid. (Yield: 70%)
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.Cl.[Cl:11][C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][C:29]=1[Cl:30])[NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](F)[CH:24]=2)[N:19]=[CH:18][N:17]=1.C(O)(=O)C>CN1C(=O)CCC1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][C:29]=1[Cl:30])[NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([N:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]3=[O:3])[CH:24]=2)[N:19]=[CH:18][N:17]=1
Reactant: Oc1ccccn1
Reactant: Fc1ccc2ncnc(Nc3ccc(Cl)c(Cl)c3)c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: O=c1ccccn1-c1ccc2ncnc(Nc3ccc(Cl)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
Sodium hydride (0.24 g) was added to a solution of 2-hydroxypyridine (0.95 g) in NMP (10 ml) and the mixture was stirred at ambient temperature for 30 minutes. A mixture of a portion (3 ml) of the resultant solution and 4-(3,4-dichloroanilino)-6-fluoroquinazoline hydrochloride (0.172 g) was heated at 215° C. for 10 hours. The reaction mixture was acidified with glacial acetic acid and evaporated at 90° C. under high vacuum. The residue was chromatographed on silica using a mixture of methylene chloride and methanol, increasing in polarity from pure methylene chloride to a 19:1 mixture of methylene chloride: methanol as eluent. The product so obtained was triturated with a 1:1 mixture of isopropanol and ethyl acetate. The solid was filtered off, washed with ethyl acetate and dried under high vacuum to give 4-(3,4-dichloroanilino)-6-(2-oxo-1,2-dihydropyridin-1-yl)quinazoline (0.099 g); NMR Spectrum: (CD3SOCD3) 6.44 (m, 1H), 6.57 (m, 1H), 7.55-7.66 (m, 1H), 7.68 (d, 1H), 7.75-8.00 (m, 4H), 8.34 (d, 1H), 8.65 (s, 1H), 8.78 (s, 1H), 9.78 (s, 1H);
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([F:28])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:17][CH:16]2[CH3:27])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C1COCC1.[C:52]1([CH3:58])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([F:28])[CH2:20][CH2:19][N:18]([CH2:21][C:22]([CH2:58][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:23]([O:25][CH3:26])=[O:24])[CH2:17][CH:16]2[CH3:27])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CCN1CCC(F)(c2cccc(OCc3ccccc3)c2)C(C)C1
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccccc1)(Cc1ccccc1)CN1CCC(F)(c2cccc(OCc3ccccc3)c2)C(C)C1

Procedure:
This compound was prepared from methyl 3-[4-(3-benzyloxyphenyl)-4-fluoro-3-methylpiperidin-1-yl]propionate and 2.5 equivalents of both lithium hexamethyldisilazide and benzyl bromide as described in Step 2 of Example 4 with the exception that THF was used as the reaction solvent as opposed to toluene. The desired compound was obtained in 42% overall yield.
Reaction SMILES: CC([NH:4]P([O:9][C:10]1[CH:15]=CC(Cl)=CC=1Cl)(OC)=S)C.[OH-].[Na+].CC(=O)OCC.CC[N:28]([C:31](C1C=CC=C(C)C=1)=[O:32])CC>O>[NH2:28][C:31]([O:9][CH2:10][CH3:15])=[O:32].[NH2:28][C:31]([NH2:4])=[O:32]
Reactant: COP(=S)(NC(C)C)Oc1ccc(Cl)cc1Cl
Reactant: CCN(CC)C(=O)c1cccc(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(N)=O
Product: NC(N)=O
Reaction time: 0.25 h

Procedure:
286.2 g of Rucoflex XS-5570-55, 675.0 g of Rucoflex S-1011-35 and 20.1 g of DMPA are reacted with 132.3 g of HDI at 80° C. for 2 hours to prepare a prepolymer. The prepolymer is then dispersed in a solution of 8.4 g of NaOH and 4.8 g of EA in 1961.0 g of water. After 15 minutes, a solution of 4.7 g of EDA and 5.4 g of DETA in 150.0 g of water is added to form an aqueous poly(urethane/urea) dispersion. A finely divided dispersion having a solids content of 35.1% and a pH of 7.2 is obtained.
Reaction SMILES: O[Li].O.[CH2:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]1[CH:24]=[CH:23][N:22]2[N:25]=[CH:26][C:27]([C:28]([O:30]CC)=[O:29])=[C:21]2[CH:20]=1)[CH3:5].Cl>C(O)C.O>[CH2:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]1[CH:24]=[CH:23][N:22]2[N:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[C:21]2[CH:20]=1)[CH3:5]
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3OCC)cc12
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CCO
Product: CCOc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2c1
Reaction time: 8 h

Procedure:
1M aq. solution of LiOH.H2O (0.4 mL) was added to a stirred solution of (R)-ethyl 5-(2-(2-ethoxy-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (Int-77) (0.12 g, 0.32 mmol) in ethanol (5 mL) and the stirring was continued at 90° C. for 8 h. The reaction mixture was concentrated under reduced pressure to afford the crude, which was diluted with cold water (20 mL) and acidified with 2N HCl solution to pH=2, solid precipitated out was filtered and dried to afford the desired compound (Int-78) as yellow solid. MS (ESI): m/z 370.3 (M+H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:26][CH2:27][OH:28])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][C:13]([CH2:16][CH2:17][C:18](OCC)=[O:19])=[CH:12][C:11]=3[CH:23]([CH3:25])[CH3:24])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[CH2:1]([C:3]1([CH2:26][CH2:27][OH:28])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][OH:19])=[CH:12][C:11]=3[CH:23]([CH3:24])[CH3:25])[CH3:2]
Reactant: CCOC(=O)CCc1cc(C(C)C)c2[nH]c3c(c2c1)CCOC3(CC)CCO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCC1(CCO)OCCc2c1[nH]c1c(C(C)C)cc(CCCO)cc21
Reaction time: 18 h
Yield: 19.5 %

Procedure:
A solution of ethyl 3-(1-ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano[3,4-b]indol-6-yl)propanoate(0.18 g, 0.46 mmol) in anhydrous diethyl ether (15 ml) was stirred at room temperature under a nitrogen atmosphere. LiAlH4 (0.09 g, 2.4 mmol) was slowly added to the solution. The mixture was stirred for 18 hr, quenched with water and 5% HCl, extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography hexane/EtOAc (4:6) twice to give (31 mg) of the product (0.031 g, 20%). 1H NMR (300 MHz, CDCl3) δ 7.70 (br, NH), 7.18 (d, 1H), 6.91 (d, 1H), 4.03 (m, 2H), 3.73 (m, 4H), 3.17 (m, 1H), 2.80 (m, 6H), 2.18 (m, 1H), 1.98 (m, 3H), 1.37 (d, 6H), 1.26 (br, 1H), 0.94 (t, 3H); ESI (+) MS m/e=346 (MH+), ESI (−) MS m/e=344 (MH−).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH:5]=[C:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[O:25])[O:23][C:21](=[O:22])[C:20]2=[CH:26][C:27]=1[Cl:28]>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:16][C:17]1[CH:18]=[C:19]([C:24]([NH:1][C:2]2[CH:15]=[CH:14][CH:13]=[C:4]([CH:5]=[C:6]3[S:10][C:9](=[O:11])[NH:8][C:7]3=[O:12])[CH:3]=2)=[O:25])[C:20](=[CH:26][C:27]=1[Cl:28])[C:21]([OH:23])=[O:22]
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Reactant: Nc1cccc(C=C2SC(=O)NC2=O)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: O=C1NC(=O)C(=Cc2cccc(NC(=O)c3cc(Cl)c(Cl)cc3C(=O)O)c2)S1
Reaction time: 8 h

Procedure:
5-(3-Amino-benzylidene)-thiazolidine-2,4-dione was dissolved in THF and treated with a solution of 4,5-dichlorophthalic anhydride and a catalytic amount of DMAP. The solution was stirred for 8 hours, then filtered and concentrated under vacuum. The residue was dissolved in EtOAc and washed with water. The organic layer was concentrated to an oil and triturated with hexane to give the product as a solid which was collected by filtration.