Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH:11]1([CH2:14][C:15](=[O:18])[CH:16]=[CH2:17])[CH2:13][CH2:12]1>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH:11]2[CH2:13][CH2:12]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: C=CC(=O)CC1CC1
Solvent: CO
Product: C[C@H](NCCC(=O)CC1CC1)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
(S)-1-(4-Bromophenyl)ethanamine (3.33 g) was added to a solution of 1-cyclopropylbut-3-en-2-one (3.07 g) in methanol (10 mL). The mixture was heated to 80° C. and stirred at this temperature for 10 min. After cooling to room temperature, the mixture was concentrated to give the crude title compound which was used without further purification. Yield: 5.20 g (crude).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[C:12]([O:22]C)[N:13]3[CH2:16][CH:17]3[CH2:21][CH2:20][O:19][CH2:18]3)=[C:9]([NH2:24])[N:8]=2)[CH2:3][CH2:2]1.Cl.C(O)C.O>CO.O1CCOCC1>[NH2:24][C:9]1[N:8]=[C:7]([O:6][CH2:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:22])[N:13]2[CH2:16][CH:17]1[CH2:21][CH2:20][O:19][CH2:18]1
Reactant: COc1nc2c(N)nc(OCCC3CC3)nc2n1CC1CCOC1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: Nc1nc(OCCC2CC2)nc2c1[nH]c(=O)n2CC1CCOC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring suspension of 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-9-(tetrahydro-3-furanylmethyl)-9H-purin-6-amine (814 mg) in methanol (3 ml) was added 4N HCl in dioxan (3 ml). After 3 h, the solvents were evaporated and the residue treated with water and neutralised by addition of saturated sodium bicarbonate with stirring. The resulting cream coloured solid was filtered off, washed with water and dried. The material was suspended in 1:1 ethanol:water (42 ml) but did not dissolve on boiling/stirring. Complete solution was obtained on adding a further 10 ml ethanol. More water (3 ml) was added and the clear solution allowed to cool to room temperature with stirring. The resulting cream coloured solid was filtered, washed with 1:1 ethanol:water (10 ml) and dried, yield 537 mg.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=1.Cl[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:12]=1
Reactant: CCOC(=O)CCl
Reactant: O=Cc1cccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cccnc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 45.8 %

Procedure:
According to the procedure of B. A. Lefker, W. A. Hada, P. J. McGarry Tetrahedron Lett. 1994, 35, 5205-5208, a solution of sodium bis(trimethylsilyl)amide (1.0 N in THF, 44.3 mL, 44.3 mmol) was added dropwise at a rate to keep the temperature below -50° C. to a stirred solution of 3-pyridine carboxaldehyde (4.41 mL, 46.7 mmol), ethyl chloroacetate (4.93 mL, 46.7 mmol) and THF (34 mL) under a dry nitrogen atmosphere. After 45 min at -78° C., the reaction mixture was warmed to 0° C. and then quenched with water and concentrated. The residue was partitioned between ether and water. The ether phase was dried with brine and concentrated. The residue was dissolved in erthyl acetate and palladium hydroxide on carbon (wet, Degussa type, 20% Pd content, 1 g) was added. The mixture was hydrogenated at 45 psi hydrogen pressure for 2 h. The reaction mixture was filtered thru sulka floc and the solvent was removed. The residue was flash chromatographed (2:3 petroleum ether:ethyl acetate, eluent) to provide the title compound as an oil (3.83 g, 42%): NMR (CDCl3); 8.24 (m, 2 H), 7.60 (d, 1 H), 7.22 (dd, 1 H), 4.45 (t, 1 H), 4.22 (q, 2 H), 3.15 (dd, 1 H), 2.95 (dd, 1 H), 1.27 (t, 3 H).
Reaction SMILES: [C:1](Cl)(=[O:14])[O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[CH3:13].[Cl-].[CH:17]1([O:23][C:24]([C:26]2[N:27]=[C:28]([CH:31]3[CH2:36][CH2:35][NH2+:34][CH2:33][CH2:32]3)[S:29][CH:30]=2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C.O>ClCCl>[CH:17]1([O:23][C:24]([C:26]2[N:27]=[C:28]([CH:31]3[CH2:32][CH2:33][N:34]([C:1]([O:2][C:3]4[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=4[CH3:13])=[O:14])[CH2:35][CH2:36]3)[S:29][CH:30]=2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1ccc(C(F)(F)F)cc1OC(=O)Cl
Reactant: O=C(OC1CCCCC1)c1csc(C2CC[NH2+]CC2)n1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(F)(F)F)cc1OC(=O)N1CCC(c2nc(C(=O)OC3CCCCC3)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, 2-methyl-5-(trifluoromethyl)phenyl chlorocarbonate (239 mg) is added to a solution of 4-{4-[(cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (VII-1, 324 mg) and diisopropylethylamine (323 mg) in dichloromethane (8 ml). The mixture is stirred at room temperature overnight, and water is then added. The aqueous phase is separated off and extracted with ethyl acetate, and the combined organic phases are then dried with sodium sulphate. The solid is filtered off and the solvent is removed by distillation. The residue is purified chromatographically. This gives 2-methyl-5-(trifluoromethyl)phenyl 4-{4-[(cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (193 mg, 39%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][C:25]1[NH:29][N:28]=[C:27]([C:30](O)=[O:31])[CH:26]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:30]([C:27]5[CH:26]=[C:25]([CH3:24])[NH:29][N:28]=5)=[O:31])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: Cc1cc(C(=O)O)n[nH]1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4cc(C)[nH]n4)nc3cc21

Procedure:
5-Methyl-1H-pyrazole-3-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 5-methyl-1H-pyrazole-3-carboxylic acid (111 mg, 0.89 mmol). The title compound was obtained as light brown powder (72 mg, 21%).
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[CH3:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]([OH:39])=O)=[CH:35][CH:36]=1>>[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:18])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:39])=[CH:33][CH:32]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Product: Cc1ccc(C(=O)N(C)[C@H](Cc2ccccc2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)cc1

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with p-toluic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(4-methylbenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 484 (M+H)+.
Reaction SMILES: C(O[N:19]1[C:24](=O)[CH2:23][CH2:22][C:20]1=O)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.Cl.N[C@@H:28](CC=CC)[C:29]([OH:31])=[O:30].C([O-])(O)=O.[Na+].Cl>CC(C)=O.O>[CH2:24]([NH:19][CH2:28][C:29]([OH:31])=[O:30])[CH:23]=[CH:22][CH3:20]
Reactant: CC=CC[C@H](N)C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC=CCNCC(=O)O
Yield: 211.3 %

Procedure:
2-N-Fluorenylmethoxycarbonylaminohex-4-enoic acid 100 was prepared according to the procedure described by Paquet.230 Fmoc-OSu (2.36 g, 7.00 mmol) was added to a stirred suspension of L-crotylglycine.HCl 101 (1.16 g, 7.03 mmol) and NaHCO3 (2.95 g, 35.0 mmol) in a mixture of acetone:water (1:1, 30 mL). The resultant suspension was stirred at room temperature for 15 h. The reaction mixture was then acidified with concentrated HCl (pH 2) and the acetone was removed under reduced pressure. The resultant suspension was extracted into DCM (3×25 mL) and the combined organic extract was washed with dilute HCl solution (1 M, 2×25 mL), water (2×25 mL), dried (MgSO4) and evaporated under reduced pressure to afford the titled Fmoc-amino acid 100 as colourless solid (1.91 g, 78%), m.p. 119-121° C. νmax (KBr): 3390bm, 3033m, 2961s, 2357w, 1730s, 1651w, 1505w, 1450w, 1395w, 850w cm−1. 1H n.m.r. (300 MHz, CDCl3): δ 1.67 (d, J=6.2 Hz, 3H, H6), 2.37-2.69 (m, 2H, H3), 4.23 (t, J=6.8 Hz, 1H, H9′), 4.42-4.48 (m, 3H, CH2O, H2), 5.30-5.37 (m, 2H, H5, NH), 5.61 (m, 1H, H4), 7.31 (td, J=7.2, 1.3 Hz, 2H, H2′, 7′), 7.34 (td, J=7.4, 1.5 Hz, 2H, H3′, 6′), 7.60 (d, J=7.3 Hz, 2H, H1″, 8′), 7.74 (d, J=7.0 Hz, 2H, H4′, 5′), one exchangeable proton (OH) not observed. 13C n.m.r. (75 MHz, CDCl3): δ 16.7 (C6), 34.1 (C3), 46.2 (C9′), 52.3 (C2), 66.2 (CH2O), 118.9 (C5), 123.0 (C2′, 7′), 124.6 (C3′, 6′), 125.2 (C1′, 8′), 127.5 (C4′, 5′), 129.7 (C4), 140.3 (C8′a, 9′a), 142.7 (C4′a, 4′b), 154.9 (OCONH), 175.0 (C1). Mass Spectrum (ESI+, MeOH): m/z 352.1 (M+H)+, C21H22NO4 requires 352.2. Spectroscopic data were in agreement with those reported in the literature.146
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([CH3:20])[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH3:18][N:16]1[CH:17]=[C:12]([C:4]2[CH:3]=[C:2]([O:1][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=2)[CH:13]=[C:14]([CH3:20])[C:15]1=[O:19]
Reactant: Cc1cc(-c2cc(O)cc(S(C)(=O)=O)c2)cn(C)c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(OCc3ccccc3)cc(S(C)(=O)=O)c2)cn(C)c1=O
Temperature: 80 °C
Yield: 24.5 %

Procedure:
A capped mixture of 5-(3-hydroxy-5-methylsulfonylphenyl)-1,3-dimethylpyridin-2-one (25 mg, 0.085 mmol), benzyl bromide (20 mg, 0.12 mmol), and Na2CO3 (18 mg, 0.17 mmol) in DMF (600 uL) was heated to 80° C. for 90 min. The mixture was filtered and the filter cake was washed with ACN (500 uL), the filtrate was purified by prep-HPLC to afford the title compound (8 mg, 25%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.08-2.13 (m, 3H) 3.26-3.28 (m, 3H) 3.51-3.57 (m, 3H) 5.22-5.34 (m, 2H) 7.33-7.47 (m, 4H) 7.48-7.53 (m, 2H) 7.54-7.60 (m, 1H) 7.67-7.71 (m, 1H) 7.83-7.88 (m, 1H) 8.17-8.22 (m, 1H). LCMS (M+H)+=384.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-])=O)[C:5]([CH3:10])=[C:6]([O:8][CH3:9])[CH:7]=1.ClC1C(B2OC(C)(C)C(C)(C)O2)=CC=CC=1N>>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[C:4]([CH:3]=1)[NH2:11]
Reactant: COc1cc(Br)cc([N+](=O)[O-])c1C
Agent: CC1(C)OB(c2cccc(N)c2Cl)OC1(C)C
Product: COc1cc(Br)cc(N)c1C

Procedure:
This material was prepared from 5-bromo-1-methoxy-2-methyl-3-nitrobenzene following the procedure used for SM-9, step 2: LCMS (m/z): 216.0 (MH+); tR=0.65 minute.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]1(O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1cccc(O)c1
Reactant: OC1CCCCC1
Product: O=Cc1cccc(OC2CCCCC2)c1

Procedure:
3-Hydroxybenzaldehyde, purchased from Acros, and cyclohexanol were processed under Mitsunobu conditions, as described in Saccomano, et al., J. Med. Chem. 34, (1991) 291-298, to provide the title compound.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:22]([C@H:24]([C@@H:26]([OH:42])[C@@H:27]([CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([OH:38])[C:32]=1[C:39]([OH:41])=[O:40])[CH3:28])[CH3:25])=[O:23])[C@H:4]1[O:8][C@@:7]([C@@H:11]2[O:16][C@@H:15]([CH3:17])[C@@:14]([OH:20])([CH2:18][CH3:19])[CH2:13][CH2:12]2)([CH2:9][CH3:10])[CH2:6][C@@H:5]1[CH3:21].[BH4-].[Na+]>>[CH3:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][CH:27]([CH3:28])[CH:26]([OH:42])[CH:24]([CH3:25])[CH:22]([OH:23])[CH:3]([CH2:2][CH3:1])[CH:4]2[CH:5]([CH3:21])[CH2:6][C:7]([CH2:9][CH3:10])([CH:11]3[CH2:12][CH2:13][C:14]([CH2:18][CH3:19])([OH:20])[CH:15]([CH3:17])[O:16]3)[O:8]2)=[C:32]([C:39]([OH:41])=[O:40])[C:33]=1[OH:38]
Reactant: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@H](C)CCc1ccc(C)c(O)c1C(=O)O)[C@H]1O[C@](CC)([C@H]2CC[C@](O)(CC)[C@H](C)O2)C[C@@H]1C
Agent: [BH4-]
Agent: [Na+]
Product: CCC(C(O)C(C)C(O)C(C)CCc1ccc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C
Reaction time: 8 h

Procedure:
To a solution of 10 g of crystalline antibiotic X-537A in 500 ml of absolute ethanaol was added 1.36 g of NaBH4. The reaction was followed by assaying with thin layer chromatography (silica gel - CHCl3 /acetone 8:2) and the reaction was continued overnight after adding an additional 1.0 g of NaBH4. The following morning the solvent was removed under reduced pressure and the heavy oil diluted with methylene chloride, washed with dilute HCl, dried (Na2SO4), and concentrated to a solid foam. The slightly pink solid was chromatographed on a 500 g silica gel column eluting with 2 l. hexane-methylene chloride (1:1), 2 l. methylene chloride 2 l. methylene chloride 2 l. methylene chloride ether (1:1). The 250 ml fractions were assayed by TLC and fractions 13-17 pooled, concentrated to a yellow solid and rechromatographed on a 150 g florisil column eluting with a gradient from hexane to acetone. The fractions containing 3-methyl-6-{4,6-dihydroxy-3,5-dimethyl-7-ethyl-7-[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl]heptyl} salicylic acid were pooled and concentrated to a small volume from which pure 3-methyl-6-{4,6-dihydroxy-3,5-dimethyl-7-ethyl-7-[ 5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl]heptyl} salicylic acid crystals were recovered, m.p. 151°-153°. From the mother liquor, additional material was crystallized, [α]D25 +0.83 (C=.60%, CH3OH).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][N:16]=1>COCCOC.C(=O)(O)[O-].[Na+]>[N:10]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:2][N:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=12
Reactant: Nc1cnccn1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1cn2ccncc2n1
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 22.4 %

Procedure:
Ethyl bromopyruvate (2.153 g, 11.04 mmol) was added to a solution of 3-aminopyrazine (1 g, 10.51 mmol) in DME (10 mL) and the mixture was stirred continuously at 20-35° C. for 2 h. The reaction mixture was filtered and the solid which precipitated out was dried well, dissolved in EtOH (10 mL) and stirred under reflux for 2 h. This reaction mixture was then concentrated under reduced pressure to obtain a crude residue. The residue was diluted with aqueous sodium bicarbonate solution, and extracted with chloroform. The organic layer separated was washed with water and then with brine solution; dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product. The crude product was further purified by column chromatography (using Silica gel 60-120 mesh and 60% EtOAc in Hexane as eluent) to afford 450 mg of the title compound the as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:4]2[N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:5]2[N:9]=[C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: C1COCCN1
Reactant: Clc1cc(Cl)n2nc(-c3cccs3)cc2n1
Solvent: C1COCCO1
Product: Clc1cc(N2CCOCC2)n2nc(-c3cccs3)cc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
There was dissolved, in 1,4-dioxane (4 mL), 5,7-dichloro-2-thiophen-2-yl-pyrazolo[1,5-a]pyrimidine (184 mg, 0.679 mM), then morpholine (118 μL, 1.36 mM) was added to the solution and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off from the reaction mixture, the residue was diluted with water and then extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was then distilled off and the resulting solid was washed with methanol to thus give the title compound (114 mg, yield: 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:14]([O:17][C:18]([C:20]1[CH:37]=[CH:36][CH:35]=[CH:34][C:21]=1[CH2:22][NH:23][C:24]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27])=[O:19])[CH:15]=[CH2:16]>>[CH2:14]([O:17][C:18]([C:20]1[CH:37]=[CH:36][CH:35]=[CH:34][C:21]=1[CH2:22][N:23]1[C:24]2[C:25](=[CH:29][CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:26](=[O:27])[N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[C:12]1=[O:13])=[O:19])[CH:15]=[CH2:16]
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: C=CCOC(=O)c1ccccc1CNc1cc(Cl)ccc1C(=O)O
Product: C=CCOC(=O)c1ccccc1Cn1c(=O)n(S(=O)(=O)c2ccc(Cl)cc2)c(=O)c2ccc(Cl)cc21
Yield: 47.6 %

Procedure:
1.38 g (6.36 mmol) of 4-chlorobenzenesulfonylisocyanate and 2.00 g (5.78 mmol) of 2-(2-allyloxycarbonylbenzyl)amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 1.50 g of the above-identified compound (yield 47.6%). Properties: colorless crystal, Melting point: 155°-156° C., PMR (δppm, DMSO-d6):4.83 (2H,d), 5.2-5.5 (4H,m), 6.0-6.2 (1H,m), 7.1-7.2 (2H,m), 7.3-7.5 (5H,m), 7.7-7.8 (2H,m), 7.9-8.1 (2H,m), 8.1-8.2 (2H,m)
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:25])[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([OH:24])=[CH:9][CH:10]=2)[O:5]1.Cl[CH2:27][C:28]#[N:29].CCOCC>CN(C)C=O>[C:28]([CH2:27][O:24][C:8]1[CH:7]=[C:6]2[C:11]([CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[CH:15]=3)[CH2:13][C:4]([CH3:25])([CH3:3])[O:5]2)=[CH:10][CH:9]=1)#[N:29]
Reactant: N#CCCl
Reactant: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(O)cc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(OCC#N)cc2O1
Temperature: 60 °C

Procedure:
Sodium hydride (0.93 g, 80% dispersion in oil) was added to a solution of 2,2-dimethyl-4-(3-trifluoromethylphenyl)chroman-7-ol (containing 1 mole of carbon tetrachloride of crystallisation) (7.5 g) in dimethylformamide (25 ml). Chloroacetonitrile (1.76 g) was added and the mixture heated at 60° C. for 3 hours. The solvent was removed under reduced pressure and the resulting oil was poured into water. The aqueous solution was extracted with ether and the etheeal extracts were dried (MgSO4) and evaporated under reduced pressure to yield an oil. Chromatography on alumina with ether--petrol (40°-60° C.); 1:3 as eluate gave the title compound which crystallised on standing.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][N:18]=3)=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:27]1[C:28]2[CH:29]=[C:30]3[O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][O:37][C:31]3=[CH:32][C:33]=2[N:34]=[CH:35][N:36]=1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:27]4[C:28]5[CH:29]=[C:30]6[O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][O:37][C:31]6=[CH:32][C:33]=5[N:34]=[CH:35][N:36]=4)=[CH:19][N:18]=3)=[CH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(Nc2ccc(F)cc2)ncc(-c2ccc(O)cn2)c1=O
Reactant: Clc1ncnc2cc3c(cc12)OCCOCCOCCO3
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(Nc2ccc(F)cc2)ncc(-c2ccc(Oc3ncnc4cc5c(cc34)OCCOCCOCCO5)cn2)c1=O
Temperature: 25 °C
Yield: 93.6 %

Procedure:
2-(4-Fluoro-phenylamino)-5-(5-hydroxy-pyridin-2-yl)-3-methyl-3H-pyrimidin-4-one (2.18 g, 7 mmol) was dissolved in dry DMF (30 ml) to which was added 60% NaH (774 mg, 19.3 mmol). After the mixture was stirred at room temperature for several minutes, a suspension of 4-Chloro-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1,3-diaza-cyclododeca[b]-naphthalene (2.08 g, 6.7 mmol) in dry DMF (40 ml) was added. The reaction mixture was stirred at room temperature for 1-2 hrs, then diluted with EtOAc and washed with sat'd NaHCO3 (3×), H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo to give crude title compound and further purification to yield product (3.68 g, 90%). 1HNMR (400 MHz, DMSO): 9.18 (s, 1H), 8.60 (m, 3H), 8.45 (d, 1H), 7.84 (s, 1H), 7.82 (m, 1H), 7.55 (m, 3H), 7.21 (m, 2H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H). LC/MS Calcd for (M+H)+587.6. found 587.9.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][N:6]([CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:14][N:15]([CH3:35])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[C:31]3[C:26](=[CH:27][C:28]([N:32]([CH3:34])[CH3:33])=[CH:29][CH:30]=3)[C:24](=[O:25])[O:23]2)=[CH:18][CH:17]=1>[Cl-].[Zn+2].[Cl-]>[CH3:5][N:6]([CH3:13])[C:7]1[CH:12]=[CH:11][C:10]([CH:22]([C:31]2[CH:30]=[CH:29][C:28]([N:32]([CH3:33])[CH3:34])=[CH:27][C:26]=2[C:24]([OH:25])=[O:23])[C:19]2[CH:18]=[CH:17][C:16]([N:15]([CH3:14])[CH3:35])=[CH:21][CH:20]=2)=[CH:9][CH:8]=1
Reactant: CN(C)c1ccccc1
Reactant: CN(C)c1ccc(C2OC(=O)c3cc(N(C)C)ccc32)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Zn+2]
Product: CN(C)c1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2C(=O)O)cc1

Procedure:
Proceeding in a manner similar to that described in part A above, but replacing the anhydrous zinc chloride with 9.3 g of anhydrous aluminum chloride, 70.0 ml of N,N-dimethylaniline and 14.9 g of 3-(4-dimethylaminophenyl)-6-dimethylaminophthalide, prepared as described in Example 1, part A above were interacted to obtain 16.1 g of 2-[4,4'-bis(dimethylamino)-benzhydryl]-5-dimethylaminobenzoic acid, a light blue powder which melted at 209°-213° C.