Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].Cl[CH2:19][CH2:20][CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:19][CH2:20][CH2:21][CH2:22][OH:23]
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: OCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reaction time: 18 h
Yield: 28.4 %

Procedure:
A solution of 33.9 grams (0.126 mole) of 2,6-dichloro-4-phenylmethoxyphenol (known compound), 16.4 grams (0.151 mole) of 4-chlorobutan-1-ol and 20.9 grams (0.151 mole) of potassium carbonate in 300 mL of DMF was warmed to 80° C. where it stirred during an 18 hour period. After this time the reaction mixture was concentrated under reduced pressure to a residue. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water and then with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using a mixture of 1:1 ethyl acetate and hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 12.2 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[C:37]([F:39])[C:36]([S:40](=[O:59])(=[O:58])[N:41](CC3C=CC(OC)=CC=3OC)[C:42]3[S:46][N:45]=[CH:44][N:43]=3)=[CH:35][C:34]=2[F:60])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][N:14]=[C:13]([N:16](C(OC(C)(C)C)=O)[C:17](OC(C)(C)C)=O)[C:12]=3[CH:31]=2)[CH:7]=1.ClC1C=CC(OC2C=C(F)C(S(=O)(=O)N(CC3C=CC(OC)=CC=3OC)C3SN=CN=3)=CC=2F)=C(C2C=CC3ON=C(N(C)C(=O)OC(C)(C)C)C=3C=2)C=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[C:34]([F:60])=[CH:35][C:36]([S:40]([NH:41][C:42]3[S:46][N:45]=[CH:44][N:43]=3)(=[O:59])=[O:58])=[C:37]([F:39])[CH:38]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][N:14]=[C:13]([NH:16][CH3:17])[C:12]=3[CH:31]=2)[CH:7]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4onc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c4c3)cc2F)c(OC)c1
Agent: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4onc(N(C)C(=O)OC(C)(C)C)c4c3)cc2F)c(OC)c1
Product: CNc1noc2ccc(-c3cc(Cl)ccc3Oc3cc(F)c(S(=O)(=O)Nc4ncns4)cc3F)cc12
Yield: 75 %

Procedure:
Following the procedure as described in EXAMPLE 44, making non-critical variations to replace di-tert-butyl [5-(5-chloro-2-{4-[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)sulfamoyl]-2,5-difluorophenoxy}phenyl)-1,2-benzoxazol-3-yl]imidodicarbonate with tert-butyl (5-(5-chloro-2-(4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2,5-difluorophenoxy)phenyl)benzo[d]isoxazol-3-yl)(methyl)carbamate, 4-(4-chloro-2-(3-(methylamino)benzo[d]isoxazol-5-yl)phenoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide was obtained as an off-white solid in 75% yield over two steps (0.21 g): 1H NMR (300 MHz, DMSO-d6) δ8.52 (s, 1H), 7.95 (d, J=1.1 Hz, 1H), 7.72 (dd, J=9.9, 6.5 Hz, 1H), 7.65 (dd, J=8.7, 1.6 Hz, 1H), 7.61 (d, J=2.6 Hz, 1H), 7.52-7.46 (m, 2H), 7.28 (d, J=8.7 Hz, 1H), 7.14 (dd, J=10.4, 6.5 Hz, 1H), 7.04-6.97 (m, 1H), 2.86 (s, 3H), (NH not observed); MS (ES+) m/z 549.6 (M+1), 551.6 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.N1C=CC=CC=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:1][CH:2]2[CH2:6][CH2:5][O:4][CH2:3]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: OC1CCOC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCOC2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 80.3 %

Procedure:
A stirred solution of 10.0 g (0.11 mole) of 3-hydroxytetrahydrofuran in 36.0 g (0.46 mole) of pyridine was cooled in an ice bath and 22.0 g (0.12 mole) of 4-methylphenylsulfonyl chloride was added. Upon complete addition, the reaction mixture was stirred at ambient temperature for 60 hours. The reaction mixture was poured into ice-water, and the mixture extracted with diethyl ether. The combined ether extracts were washed several times with water. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 21.4 g of 3-tetrahydrofuranyl 4-methylphenylsulfonate.
Reaction SMILES: Cl.[N:2]1[N:3]=[CH:4][N:5]2[CH:10]=[CH:9][N:8]=[C:7]([N:11]3[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12]3)[C:6]=12.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[N:27][C:26]([C:29](O)=[O:30])=[N:25]2)=[CH:20][CH:19]=1.C(N(CC)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[N:2]1[N:3]=[CH:4][N:5]2[CH:10]=[CH:9][N:8]=[C:7]([N:11]3[CH2:15][CH2:14][C@H:13]([NH:16][C:29]([C:26]4[N:27]=[CH:28][N:24]([C:21]5[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=5)[N:25]=4)=[O:30])[CH2:12]3)[C:6]=12
Reactant: O=C(O)c1ncn(-c2ccc(F)cc2)n1
Reactant: N[C@H]1CCN(c2nccn3cnnc23)C1
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCN(c2nccn3cnnc23)C1)c1ncn(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
To a suspension of (S)-1-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyrrolidin-3-amine hydrochloride salt (63 mg, 0.23 mmol), 1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxylic acid (42 mg, 0.2 mmol) in DMF (5 mL) was added diethylisopropyl amine (650 mg, 5 mmol), followed by HATU (76 mg, 0.2 mmol). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solutions of KH2PO4 and NaHCO3, followed by brine. The organic layer was concentrated in vacuo and the residue purified by reverse phase HPLC (acetonitrile-H2O with 0.1% TFA as eluent) to give 32 mg of the title compound (40% yield) as white solid.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([C:9]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[CH2:13][CH:12]2[CH2:21][CH3:22])=[O:10])[CH:4]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:39](=[CH:40][CH:41]=1)[CH2:38][C:28]1([C:36]3[C:31](=[N:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]1=[O:37])[CH2:27]2>CC(O)CCC>[CH2:21]([CH:12]1[CH2:13][C:14]2[C:19](=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:11]1[C:9]([C:5]1[N:6]=[CH:7][N:8]=[C:3]([NH:23][C:24]2[CH:25]=[C:26]3[C:39](=[CH:40][CH:41]=2)[CH2:38][C:28]2([C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]2=[O:37])[CH2:27]3)[CH:4]=1)=[O:10])[CH3:22]
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: CCC1Cc2ccc(F)cc2N1C(=O)c1cc(Cl)ncn1
Agent: Cl
Solvent: CCCC(C)O
Product: CCC1Cc2ccc(F)cc2N1C(=O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1

Procedure:
63 μL (0.25 mmol) 4M aqueous hydrochloric acid were added to 516 mg (2.00 mmol) (6-chloro-pyrimidin-4-yl)-(2-ethyl-6-fluoro-2,3-dihydro-indol-1-yl)-methanone and 611 mg (2.00 mmol) 5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one in 10 mL of 2-pentanol. The reaction mixture was refluxed for 6 h. The reaction mixture was evaporated down using the rotary evaporator and the residue was taken up in DMF. The purification was carried out by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: O.[C:2]([OH:14])(=[O:13])[CH2:3][C:4]([CH2:9][C:10]([OH:12])=[O:11])([C:6]([OH:8])=[O:7])[OH:5].[Cl:15][C:16]1[N:17]=[C:18]([CH3:39])[N:19]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:32]3[N:37]=[CH:36][C:35]([F:38])=[CH:34][N:33]=3)[CH2:28][CH2:27]2)[C:20]=1[Cl:21]>C(O)C>[C:2]([OH:14])(=[O:13])[CH2:3][C:4]([CH2:9][C:10]([OH:12])=[O:11])([C:6]([OH:8])=[O:7])[OH:5].[Cl:15][C:16]1[NH:17][C:18](=[CH2:39])[N:19]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][N:29]([C:32]3[N:37]=[CH:36][C:35]([F:38])=[CH:34][N:33]=3)[CH2:30][CH2:31]2)[C:20]=1[Cl:21]
Reactant: Cc1nc(Cl)c(Cl)n1CCCCN1CCN(c2ncc(F)cn2)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CCO
Product: C=C1NC(Cl)=C(Cl)N1CCCCN1CCN(c2ncc(F)cn2)CC1
Yield: 90.3 %

Procedure:
1.1 g (5.2 mmol) of citric acid monohydrate are added to a solution of 2 g (5.2 mol) of 2-{4-[4-(4,5-dichloro-2-methylimidazol-1-yl)butyl]piperazin-1-yl}-5-fluoropyrimidine in absolute ethanol. After a certain period of time, 2.72 g (91% yield) of 2-{4-[4-(4,5-dichloro-2-methlylimidazol-1-yl)butyl]piperazin-1-yl}-5-fluoropyrimidine citrate precipitate in the form of a solid with an M.p. of 151-153° C.
Reaction SMILES: [F:1][C:2]1[CH:11]2[CH:6]([CH2:7][CH2:8][C:9](=[O:12])[NH:10]2)[CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:20])C(=O)C1>>[Br:20][C:4]1[CH:3]=[C:2]([F:1])[CH:11]2[CH:6]([CH2:7][CH2:8][C:9](=[O:12])[NH:10]2)[CH:5]=1
Reactant: O=C1CCC2C=CC=C(F)C2N1
Reactant: O=C1CCC(=O)N1Br
Product: O=C1CCC2C=C(Br)C=C(F)C2N1

Procedure:
This intermediate was obtained according to general procedure I from 8-fluoro-3,4,4a,8a-tetrahydro-1H-quinolin-2-one (515 mg, 3.12 mmol) and NBS (583 mg, 3.27 mmol) after flash chromatography on silica gel (hexanes/ethyl acetate, 5/1, Rf=0.32) as white solid (647 mg, 2.65 mmol, 85%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:13]([Cu])#[N:14].Cl>CN(C=O)C>[C:13]([C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:14]
Reactant: COC(=O)c1cc(Br)ccc1O
Reactant: N#C[Cu]
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C#N)ccc1O
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Methyl 5-bromo-2-hydroxybenzoate (190.8 g; from step (a) above) and CuCN (73.9 g) were refluxed in DMF (500 mL) for 7 h. The temperature was allowed to decrease to 80° C. and HCl (500 mL) and FeCl3 (165.0 g) were added. The reaction mixture was stirred for 30 min., concentrated and partitioned between H2O and DCM. The organic layer was dried, concentrated the residue recrystallized from methylethyl ketone giving the sub-title compound in a 61% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH2:18][OH:19])=[O:15])[C:5]2=[O:20].[P:21](O)([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH2:18][O:19][P:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:22])=[O:15])[C:5]2=[O:20]
Reactant: CCn1cc(C(=O)OCCO)c(=O)c2cc(Br)cnc21
Reactant: O=P(O)(OCc1ccccc1)OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCn1cc(C(=O)OCCOP(=O)(OCc2ccccc2)OCc2ccccc2)c(=O)c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.4 %

Procedure:
2-Hydroxyethyl 6-bromo-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 23, 100 mg, 0.29 mol), dibenzyl hydrogen phosphate (65 mg, 0.23 mmol) and triphenylphosphine (192 mg, 0.733 mmol) were dissolved in tetrahydrofuran (15 mL). Diisopropyl azodicarboxylate [DIAD] (106 mg, 0.52 mmol) was added drop wise and the mixture was stirred for 4 h at room temperature. The reaction mixture was concentrated under reduced pressure and water (100 mL) was added. The aqueous mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give a crude compound. The crude compound was purified by flash column chromatography over silica gel (10-50% ethyl acetate/petroleum ether) to afford 60 mg (40%) of 2-{[bis(benzyloxy)phosphoryl]oxy}ethyl 6-bromo-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate.
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.[CH2:12]([C:14]1[CH:15]=[C:16]([CH3:26])[C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:18][CH:19]=1)[CH3:13]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[C:16]([CH3:26])=[CH:15][C:14]([CH2:12][CH3:13])=[CH:19][N:18]=3)[CH2:21][CH2:22]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Reactant: Cc1cc(Br)ccc1C(=O)O
Product: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Yield: 85 %

Procedure:
Using 4-bromo-2-methylbenzoic acid (1.42 g) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (1.23 g) described in Preparation Example 81 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (2.05 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]([C:19]4[S:20][CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[N:23]=4)=[O:18])=[CH:13][C:12]=23)[CH:5]=[CH:6][CH:7]=1>O.C1COCC1>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[S:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=2)=[O:18])=[CH:13][C:12]=1[C:8](=[O:9])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C(c1ccc2noc(-c3cccc(Cl)c3)c2c1)c1nc(-c2ccccc2)cs1
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(C(=O)c2nc(-c3ccccc3)cs2)cc1C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
TiCl3 15% in water (300 ml) was added slowly at room temperature to a mixture of intermediate (15) (0.0656 mol) in THF (500 ml). The mixture was stirred at room temperature overnight, then poured out into ice water, extracted with DCM and washed with K2CO3 10%. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness, yielding 25.5 g (92.7%) of [4-amino-3-(3-chlorobenzoyl)phenyl](4-phenyl-2-thiazolyl)-methanone (intermediate 16).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8][CH2:9][C:10]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C.C(O)(=O)C>[CH3:1][O:2][C:3]([C@H:5]1[C@@H:10]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1=C(NCc2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NCc1ccccc1
Reaction time: 1.75 h

Procedure:
A solution of crude 4-benzylamino-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (3.86 g, approximately 10 mmol) in acetonitrile (30 mL) and acetic acid (20 mL) was stirred on an ice bath and treated with sodium triacetoxyborohydride (4.83 g, 22.5 mmol). After 1.75 hours, additional sodium triacetoxyborohydride (4.82 g, 22.5 mmol) was added. After 2.25 hours, the mixture was concentrated under vacuum, and the residue was diluted with 1.0 N aqueous sodium hydroxide (50 mL), and the mixture was stirred on ice and the pH was adjusted to 10 with 50% aqueous sodium hydroxide. The mixture was extracted with dichloromethane, and the organic phase was dried over sodium sulfate and concentrated to provide an orange gum. Purification by flash chromatography with 40% ethyl acetate in hexane provided a colorless viscous oil (2.86 g, 82% for two steps). 1H NMR (300 MHz, CDCl3) δ7.4-7.3 (m, 5H), 4.03 (m, 1H), 3.88 (ab pattern, 2H), 3.73 (m, 1H), 3.71 (s, 3H), 3.38 (m, 1H), 3.20 (m, 1H), 3.12 (m, 1H), 2.90 (m, 1H), 1.91 (m, 1H), 1.78 (m, 1H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:22])[N:8]3[CH2:21][CH2:20][CH2:19][CH:9]3[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]=2[CH:12]=1.Br[CH2:24]CCCC(Cl)=O>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:22])[N:8]3[CH2:21][CH2:20][CH2:19][CH2:24][CH:9]3[N:10]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)CCCCBr
Reactant: COc1ccc2c(c1)N(c1ccccc1)C1CCCN1C2=O
Product: COc1ccc2c(c1)N(c1ccccc1)C1CCCCN1C2=O

Procedure:
Following the procedure for 6-methoxy-4-phenyl-2,3,3a,4-tetrahydropyrrolo[2,1-b]quinazolin-9(1H)-one, using 5-bromovaleroyl chloride in place of 4-bromobutyryl chloride, the titled compound was obtained.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([CH2:21][C:22](OCC)=[O:23])#[N:20]>>[NH2:20][C:19]1[CH:21]=[C:22]([OH:23])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: CCOC(=O)CC#N
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Nc1cc(O)c2ccccc2n1
Reaction time: 1 h

Procedure:
The appropriate aniline p-toluenesulfonate and ethyl cyanoacetate are combined in equimolar quantities and heated at 225° to 260° C. until a melt resulted. (Higher temperatures are used if necessary to achieve a melt). The temperature of the melt is lowered to 240° to 250° C. and heating continued for one hour. The hot melt is poured into ice-cold chloroform (about 1 to 1.5 liters per mole of aniline reactant) and the mixture stirred for one hour. The solid is filtered off, added to water-ethanol (1 liter of 1:1 per mole of aniline reactant) at 45° to 50° C. and the solution made basic with ammonium hydroxide. The solid is separated by filtration and recrystallized from a suitable solvent such as isopropanol.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N:13]1([CH2:18][C:19]#[C:20][C:21]([OH:23])=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.[NH2:24][C:25]1[CH2:31][N:30]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)[C:28]2[CH:39]=[C:40]([CH2:46][CH3:47])[C:41]([S:43][CH2:44][CH3:45])=[CH:42][C:27]=2[N:26]=1>O1CCCC1.CN(C)C=O>[CH2:44]([S:43][C:41]1[C:40]([CH2:46][CH3:47])=[CH:39][C:28]2[C:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)=[N:30][CH2:31][C:25]3[N:26]([C:19]([CH2:18][N:13]4[CH2:14][CH2:15][CH2:16][CH2:17]4)=[CH:20][C:21](=[O:23])[N:24]=3)[C:27]=2[CH:42]=1)[CH3:45]
Reactant: CCSc1cc2c(cc1CC)C(c1ccc(C)cc1)=NCC(N)=N2
Reactant: O=C(O)C#CCN1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCSc1cc2c(cc1CC)C(c1ccc(C)cc1)=NCc1nc(=O)cc(CN3CCCC3)n1-2

Procedure:
In the manner given in Example 21, carbonyldiimidazole, 4-(1-pyrrolidinyl)tetrolic acid, and 2-amino-8-ethylthio-7-ethyl-5-(p-methylphenyl)-3H-1,4-benzodiazepine was stirred in tetrahydrofuran-dimethylformamide to give 10-ethylthio-9-ethyl-1-(1-pyrrolidinylmethyl)-7-(p-methylphenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:31](/[CH:32]=[CH:33]/[C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)=[N:30][N:29](C4CCCCO4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[Cl:40][C:37]1[CH:36]=[CH:35][C:34](/[CH:33]=[CH:32]/[C:31]2[C:17]3[C:18](=[N:19][C:20]([C:22]4[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=4)=[CH:21][C:16]=3[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])[NH:29][N:30]=2)=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(O)cc3)nc3c2c(/C=C/c2ccc(Cl)cc2)nn3C2CCCCO2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1cc(-c2ccc(O)cc2)nc2[nH]nc(/C=C/c3ccc(Cl)cc3)c12)N1CCNCC1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
To a solution of 4-[3-[(E)-2-(4-chloro-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (1.32 g, 2.05 mmol) in dry methanol (20 ml) was added 4N HCl in dioxane (5.1 ml, 20 mmol). The reaction mixture was heated to reflux for 30 minutes then cooled to room temperature and filtered. The precipitate was isolated and dried to afford a chlorhydrate salt of the title compound as an orange solid (0.9 g, 90%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:17]=[O:18].[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH:19]1([CH:17]([C:3]2[O:4][C:5]3[CH:10]=[CH:9][C:8]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[CH:7][C:6]=3[C:2]=2[CH3:1])[OH:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1c(C=O)oc2ccc(N3CCOCC3)cc12
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C(O)C2CCCCC2)oc2ccc(N3CCOCC3)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution (5 mL) of 3-methyl-5-(morpholin-4-yl)-1-benzofuran-2-carbaldehyde (0.24 g) synthesized in the above-mentioned (3) in tetrahydrofuran was added dropwise cyclohexylmagnesium bromide (2 mL, 1M tetrahydrofuran solution) under ice-cooling. After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give cyclohexyl[3-methyl-5-(morpholin-4-yl)-1-benzofuran-2-yl]methanol (0.39 g, quantitative) as a pale-yellow oil.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:12])[C@@H:9]([OH:11])[CH3:10].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(Cl)Cl>[OH:11][C@@H:9]([CH3:10])[CH2:8][O:12][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](O)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H](C)O)cc1
Temperature: -20 °C
Reaction time: 18 h

Procedure:
Triethylamine was added to methylene chloride solution of (2S)-propane-1,2-diol, and then methylene chloride solution of p-toluenesulfonyl chloride was added thereto at −20° C. and stirred at room temperature for 18 hours to obtain (2S)-2-hydroxypropyl-4-methylbenzene sulfonate.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH2:17]([O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.7 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged with 30 mL of acetonitrile. To the stirred solvent were added 2,4-dihydroxybenzaldehyde (8.0 g, 57.0 mmol), potassium carbonate (15.77 g, 114.0 mmol). The reaction mixture was brought to 0° C., was added benzyl bromide (9.905 g, 57.0 mmol) in acetonitrile (100 mL) drop wise and stirred at room temperature for 3 h. The reaction mixture was concentrated to distill off the solvent. The residue was extracted with ethyl acetate (80 mL). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product obtained as a white solid (4.0 g, yield: 30.77%).