Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]([O:14]C)=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:16]1([Li])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C1COCC1>[C:16]1([C:12]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([OH:1])[CH:11]=2)[OH:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc(O)nc2ccccc12
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Oc1cc(C(O)(c2ccccc2)c2ccccc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 194.3 %

Procedure:
A solution of methyl 2-hydroxy-4-quinolinecarboxylate (406 mg, 2 mmol) in THF (20 mL) at 0° C. was treated with a solution of phenyl lithium (1.8-M in THF, 2.3 mL, 4.2 mmol), stirred at room temperature for 2 h, poured into water (100 mL), the resulting precipitate filtered and dried to give the title compound (636 mg, 97%) as a cream solid: mp>350° C.; IR νmax (Nujol)/cm−1 3550-3300,3085, 3059, 2924, 2854, 1652, 1461, 1377, 759, 750 and 698; NMR δH (400 MHz, ?) 5.66 (1H, s), 6.88 (1H, t, J 7.6 Hz), 7.28-7.39 (11H, m), 7.47 (1H, t, J 7.5 Hz), 7.66 (1H, d, J 8.6 Hz), 7.81 (1H, d, J 7.6 Hz) and 11.63-11.88 (1H, s); M/Z 328 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([NH2:13])[C:10]([NH2:14])=[C:9]([I:15])[CH:8]=2)=[C:5]([CH3:16])[O:4][N:3]=1.[C:17](C1NC=CN=1)(C1NC=CN=1)=[O:18].N1C=CN=C1>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([I:15])[C:10]3[NH:14][C:17](=[O:18])[NH:13][C:11]=3[CH:12]=2)=[C:5]([CH3:16])[O:4][N:3]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Cc1noc(C)c1-c1cc(N)c(N)c(I)c1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(I)c2[nH]c(=O)[nH]c2c1
Temperature: 25 °C

Procedure:
A mixture of 5-(3,5-dimethylisoxazol-4-yl)-3-iodobenzene-1,2-diamine (15 g, 45.6 mmol, 1.0 eq), DMAP (2.9 g, 22.7 mmol, 0.5 eq) and carbonyl diimidazole (11.0 g, 68.4 mmol, 1.5 eq) in THF (200 mL) was refluxed for 3 h. The reaction was cooled to room temperature, purified by flash column chromatography to give a solid, which contained some imidazole and DMAP. The solid was triturated with THF (2×) and filtered to afford 6-(3,5-dimethylisoxazol-4-yl)-4-iodo-1H-benzo[d]imidazol-2(3H)-one. LC-MS: 354.0 [M−H]−1H NMR (400 MHz, DMSO-d6) δ 10.9 (br s, 2H), 7.24 (d, J=1.6 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 2.37 (s, 3H), 1.78 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([C:21](OC)=[O:22])=[N:11][C:12]([O:19][CH3:20])=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:26][NH2:27]>CO.O>[NH:26]([C:21]([C:10]1[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:14][C:13]([C:15]([F:18])([F:16])[F:17])=[C:12]([O:19][CH3:20])[N:11]=1)=[O:22])[NH2:27]
Reactant: NN
Reactant: COC(=O)c1nc(OC)c(C(F)(F)F)cc1NC(=O)OC(C)(C)C
Solvent: CO
Solvent: O
Product: COc1nc(C(=O)NN)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Yield: 97.1 %

Procedure:
A suspension of methyl 3-(tert-butoxycarbonylamino)-6-methoxy-5-(trifluoromethyl)picolinate (step 2) (3.1 g, 8.85 mmol) in dry MeOH (20 ml) was treated with hydrazine monohydrate (1.108 g, 22.12 mmol) and the suspension was heated at reflux overnight. The mixture was diluted with water and the resulting precipitate was collected by filtration and dried in a vacuum oven to afford the title compound as a light brown solid (3.01 g). LC-MS Rt=1.27 min [M+H]+ 251 [−minus Boc group] (Method HighpH_v003.).
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[NH:17]1[C:21]2[CH:22]=[C:23]([N:26]3[CH:30]([C:31]4[C:36]([F:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=4[Cl:39])[C:29]([C:40]4C=CC=CC=4)=[C:28]([OH:46])[C:27]3=[O:47])[CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1>CO.O>[NH:17]1[C:21]2[CH:22]=[C:23]([N:26]3[CH:30]([C:31]4[C:36]([F:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=4[Cl:39])[C:29]([CH3:40])=[C:28]([O:46][CH3:3])[C:27]3=[O:47])[CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1
Reactant: O=C1C(O)=C(c2ccccc2)C(c2c(F)ccc(F)c2Cl)N1c1ccc2nc[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC1=C(C)C(c2c(F)ccc(F)c2Cl)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (10 eq in water), diazald (5 eq) ethylene glycol/Et2O (3/1 v/v), 1-(1H-benzo[d]imidazol-6-yl)-5-(2-chloro-3,6-difluorophenyl)-3-hydroxy-4-phenyl-1H-pyrrol-2(5H)-one (0.103 g, 0.25 mmol, 1 eq) and MeOH/H2O (90/10 v/v); yield: 0.013 g (13.3%); MS m/z: 390.2 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 1.78, 1.81 (2s, 3H), 3.94, 3.95 (2s, 3H), 6.34-6.35 (m, 1H), 7.11-7.17 (m, 1H), 7.25-7.29 (m, 1H), 7.35-7.40 (m, 1H), 7.52-7.54 (m, 1H), 7.67 (s, 1H), 8.35 (s, 1H); HPLC (METHOD [A]): rt 12.59 min (95%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=1)#[CH:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17]([C:20]#[C:19][C:21]4[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:28])[CH3:29])=[CH:23][CH:22]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(C(C)(C)O)cc1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Product: Cc1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3ccc(C(C)(C)O)cc3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-iodo-7-methyl-pyrazolo[1,5-a]pyrimidine (example 292) (185 mg, 0.5 mmol) and 2-(4-ethynyl-phenyl)-propan-2-ol (example D.4) (80 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (94 mg, 47%). MS (ISP) 402.3 [(M+H)+]; mp 112-115° C.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([C@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][C@H:9]1[CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)=O)(C)(C)C.[C:31]1([C:37]2[N:41]=[C:40]([CH2:42][NH2:43])[NH:39][N:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:20][C@H:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@@H:12]1[NH:8][C@H:9]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH:43][CH2:42][C:40]3[NH:39][N:38]=[C:37]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:41]=3)=[O:27])=[CH:24][CH:23]=2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Reactant: NCc1nc(-c2ccccc2)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1nc(-c2ccccc2)n[nH]1)c1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid (i-1, 0.020 g, 0.049 mmol) in N,N-dimethylformamide (0.5 ml) was added to 1-(3-phenyl-1H-1,2,4-triazol-5-yl)methanamine (0.018 g, 0.073 mmol) followed by 1-hydroxybenzotriazole (0.0099 g, 0.073 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (0.014 g, 0.073 mmol) and N,N-diisopropylethylamine (0.042 ml, 0.24 mmol). The reaction mixture was stirred at ambient temperature for 4 h. The mixture was directly purified by reverse phase HPLC (TMC Pro-Pac C18; 30-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). The resulting pure fractions were lyophilized overnight to give the titled compound as a white solid. LC-MS 590.2 (M+23).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[N:29]3[CH:36]=[CH:37][CH:38]=[C:28]3[CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[CH:35]1[C:30]2[N:29]3[CH:36]=[CH:37][CH:38]=[C:28]3[CH2:27][CH2:26][N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])=[CH:40][CH:39]=3)=[O:24])[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)cc1

Procedure:
To a stirred solution of 5 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 7 mmol of triethylamine and 5 mmol of 6,7-dihydro-5-(4-aminobenzoyl)-5H-pyrrolo[1,2-a][1,5]benzodiazepine. The reaction mixture is washed with water, 2M citric acid, NaHCO3, and brine. The organic layer is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid; mass spectrum (CI):422(M+H).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([NH:11][C:12](OC(C)(C)C)=O)[C:6]([O:8]CC)=[O:7])C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].Cl[CH2:35]Cl>>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[CH2:28]([N:11]([C:5]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:4]([OH:3])=[O:26])[C:6]([OH:8])=[O:7])[CH2:12][CH3:35])[CH3:29]
Reactant: CCOC(=O)C(Cc1ccccc1)(NC(=O)OC(C)(C)C)C(=O)OCC
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(Cc1ccccc1)(C(=O)O)C(=O)O
Reaction time: 1 h

Procedure:
To the product of Step A (7.5 g, 20.52 mmol) in dichloromethane (24 mL) was added trifluoroacetic acid (12 mL, 156 mmol) and the mixture stirred for 1 h. The solvent was removed in vacuo and the oil azeotroped with toluene (2×20 mL) to afford the title compound as a tan amorphous solid. LC/MS 266.1 (M+1).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([CH2:21][C:22]5[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=5)[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:17]2[CH2:16][C:15]3[CH:14]=[N:13][C:12]4[NH:8][N:9]=[CH:10][C:11]=4[C:20]=3[CH2:19][CH2:18]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(CN2CCc3c(cnc4c3cnn4Cc3ccc(OC)cc3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1ccc(CN2CCc3c(cnc4[nH]ncc34)C2)cc1
Temperature: 65 °C

Procedure:
To 3,7-bis-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.092 g, 0.22 mmol) was added trifluoroacetic acid (3 mL). The reaction mixture was heated at 65° C. for 16 hours. On the completion of the reaction, toluene (5 mL) was added. The solvent was removed under reduced pressure to give a dark brown solid. The residue was then partitioned between EtOAc and aqueous NaOH. The organic layer was then separated, washed with brine (2×10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give a residue. The crude product was purified using flash column chromatography (SiO2, 1% methanol in EtOAc) to desired product, 7-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine as a pale yellow solid (0.047 g, 72%). M.p.=184-186° C.; 400 MHz 1H NMR (DMSO-d6) δ: 13.49 (s, 1H), 8.19 (s, 1H), 8.08 (s, 1H), 7.32-7.26 (m, 2H), 6.94-6.88 (m, 2H), 3.75 (s, 3H), 3.64 (s, 2H), 3.62 (s, 2H), 3.1-3.03 (m, 2H), 2.8-2.72 (m, 2H); LCMS [M+H]: 295.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH:5]([OH:13])[CH:6]([OH:12])[CH2:7][C:8]([O:10][CH3:11])=[O:9].[CH:15](OCC)(OCC)[O:16][CH2:17][CH3:18]>C1(C)C=CC=CC=1>[CH3:11][O:10][C:8](=[O:9])[CH2:7][CH:6]1[CH:5]([CH2:4][C:3]([O:2][CH3:1])=[O:14])[O:13][CH:15]([O:16][CH2:17][CH3:18])[O:12]1
Reactant: COC(=O)CC(O)C(O)CC(=O)OC
Reactant: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOC1OC(CC(=O)OC)C(CC(=O)OC)O1
Yield: 97.5 %

Procedure:
To a solution of 3,4-dihydroxy-hexanedioic acid dimethyl ester (Ex-14A, 8.8 g, 43 mmol) in toluene (65 mL) was added triethyl orthoformate (12.6 g, 85.4 mmol) and the mixture was heated at reflux with a Dean-Stark trap for 24 h. The reaction mixture was then distilled to remove toluene and excess triethyl orthoformate and dried in vacuo to give (2-ethoxy-5-methoxycarbonylmethyl-[1,3]dioxolan-4-yl)-acetic acid methyl ester as a colorless oil (11.0 g, 99%). This material used without further purification. 1H-NMR (300 MHz, CDCl3) δ5.80 (s, 1H),4.41 (q, 1H, J=6.3 Hz), 4.28 (q, 1H, J=6.3 Hz), 3.71 (s, 6H), 3.78 (q, 2H, J=7.2 Hz), 2.83 (dd, 1H, J=9.3, 6.7 Hz), 2.70 (dd, 1H, J=6.7, 3.0 Hz), 1.22 (t, 3H, J=7.2 Hz). HRMS (EI) calcd for C11H18O7 (M−H), 261.0974; found, 261.0970.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:26])[C:22]([Cl:34])=[CH:21][C:10]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].O.Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([C:25]([N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)=[O:26])[C:22]([Cl:34])=[CH:21][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCN(C(=O)c2cc(OCc3ccccc3)c(C(=O)OCc3ccccc3)cc2Cl)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(C(=O)c2cc(OCc3ccccc3)c(C(=O)O)cc2Cl)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of benzyl 2-(benzyloxy)-5-chloro-4-(4-methylpiperazine-1-carbonyl)benzoate (may be prepared as described in D75) (400 mg, 0.837 mmol) in tetrahydrofuran (THF) (5.00 mL) were added lithium hydroxide (63.4 mg, 2.65 mmol) and water (1.5 mL). The mixture was stirred at 40° C. for 2 hours. After cooling, 2M hydrochloric acid (1.386 mL, 2.77 mmol) was added. The solvent was removed in vacuo to give the title product as a crude solid (324 mg, assuming 100% yield).
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[C:14]3[C:9]([CH2:10][CH2:11][CH2:12][C:13]3=[O:16])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].O>CO>[N:1]1([C:6]2[CH:15]=[C:14]3[C:9]([CH2:10][CH2:11][CH2:12][CH:13]3[OH:16])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCc2ccc(N3CCCC3)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC1CCCc2ccc(N3CCCC3)cc21

Procedure:
To a solution of 7-pyrrolidin-1-yl-3,4-dihydro-2H-naphthalen-1-one (0.548 g, 2.55 mmol) in methanol (20 mL) at 0° C. is added sodium borohydride (0.241 g, 3.54 mmol) and the reaction is stirred for 1.5 hours, whereupon water is added and the volatiles are removed in vacuo. The mixture is extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered, and concentrated to give 7-pyrrolidin-1-yl-3,4-dihydro-2H-naphthalen-1-ol, which is used in the next step without further purification.
Reaction SMILES: C[O-].[Na+].[CH:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:14][C:15]1([CH3:25])[CH2:20][O:19][CH:18]([C:21](=[O:24])[CH2:22][CH3:23])[O:17][CH2:16]1>CO>[CH3:25][C:15]1([CH3:14])[CH2:16][O:17][CH:18]([C:21](=[O:24])[C:22]([CH3:23])=[CH:4][CH:5]=[CH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:19][CH2:20]1
Reactant: O=CC=Cc1ccccc1
Reactant: CCC(=O)C1OCC(C)(C)CO1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=CC=Cc1ccccc1)C(=O)C1OCC(C)(C)CO1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
7.2 g of a 30% strength by weight solution of sodium methylate in methanol were added dropwise to a solution of 52.9 g of cinnamaldehyde and 68.9 g of 5,5-dimethyl-2-propionyl-1,3-dioxane in 200 ml of methanol in the course of 15 minutes at 0-5° C., and the mixture was stirred for a further 2 hours at 0-5° C. Thereafter, the reaction solution was seeded with a few crystals of the product and stirred overnight at room temperature. After the precipitate had been filtered off under suction and washed with cold methanol, 29.8 g of the product were obtained in the form of colorless crystals of melting point 122-125° C.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9](OC)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CO.[BH4-].[Li+]>C1COCC1>[OH:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([S:2]([NH2:1])(=[O:3])=[O:4])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(CO)cc1
Temperature: 0 °C
Yield: 75.2 %

Procedure:
To a solution of methyl [4-(aminosulfonyl)]benzoate (5.8 g, 27 mmol) (Step 2) in THF (400 ml), methanol (1.6 ml, 40 mmol) and lithium borohydride (20 ml, 2M solution in THF, 42 mmol) were added over 10 minutes. After heating at reflux for 3.5 hours, the reaction mixture was cooled and poured over ice containing 1N HCl (80 ml). The reaction mixture was extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated. The crude mixture was purified by chromatography (silica gel, hexane/ethyl acetate, 1/1) to give 4-(hydroxymethyl)benzenesulfonamide (3.8 g, 75%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][C:6]2=[N:7][CH:8]=1.[H-].[Na+].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C=O)C.C1COCC1>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:9]2[C:6]3=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]3[CH:11]=[C:10]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:22][CH:21]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cc2cc(OC)cnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OC)cnc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To Ethyl 5-methoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylate isolated in step 3 (166 mg; 0.753 mmol) in DMF (2 mL) and THF (1 mL) cooled to 0° C. was added solid sodium hydride (60% dispersion in mineral oil; 40 mg, 1.00 mmol) and the solution allowed to warm to ambient temperature. 4-chlorobenzylchloride (181 mg, 1.12 mmol) was then added and the reaction maintained at ambient temperature. After completion (as determined by TLC analysis) the reaction mixture was partitioned between EtOAc and water, the aqueous layer extracted with EtOAc, the combined organic phases dried (MgSO4), filtered and evaporated. The residue was purified on silica gel eluting with a gradient of 0 to 10% EtOAc in hexanes to afford the title compound as a colorless solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:48])[CH2:30][CH2:31][N:32]([C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1)[C:33]([C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)=[O:34]>>[CH3:28][N:29]([CH3:48])[CH2:30][CH2:31][N:32]([C:41]1[CH:42]=[CH:43][C:44]([NH:45]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:46][CH:47]=1)[C:33]([C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)=[O:34]
Reactant: CN(C)CCN(C(=O)c1cccnc1)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)C(=O)c2cccnc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-(2-dimethylamino-ethyl)-N-(pyridine-3-carbonyl)-amino)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C33H31N5O4
Reaction SMILES: O[C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]2)=[CH:15][CH:14]=1
Reactant: COC(=O)[C@H]1CC[C@@H](O)CC1
Reactant: Sc1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1CC[C@H](Sc2ccc(Cl)cc2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of methyl cis-4-hydroxycyclohexanecarboxylate (500 mg, 3.16 mmol) in toluene (30 mL), 4-chlorobenzenethiol (457 mg, 3.16 mmol) and cyanomethylenetributylphosphorane (915 mg, 3.16 mmol) were added, and the resulting mixture was stirred at 100° C. for 2 hours. Then, the residue obtained by distilling off the solvent in the reaction solution under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=95:5 to 85:15 (v/v)), whereby the title compound was obtained as an oil (206 mg, yield: 26%).
Reaction SMILES: FC(F)(F)C(O)=O.C([S:11][CH2:12][CH:13]([CH2:28][CH2:29][CH2:30][NH2:31])[C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])=[O:15])(=O)C>O.N>[NH2:31][CH2:30][CH2:29][CH2:28][CH:13]([CH2:12][SH:11])[C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])=[O:15]
Reactant: CC(=O)SCC(CCCN)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N=C(N)NCCC[C@H](NC(=O)C(CS)CCCN)C(=O)O

Procedure:
Nα -(2-acetylthiomethyl-5-aminopentanoyl)-L-arginine trifluoroacetate (2 g) is dissolved in a mixture of water (25 ml) and concentrated ammonia (25 ml) and this solution is stored at room temperature for twenty minutes. The solution is concentrated in vacuo to ca. 5 ml and applied to a column of Dowex 50 ion exchange resin (50 ml) in the hydrogen cycle. After washing with water Nα -[5-amino-2-mercaptomethylpentanoyl)-L-arginine is eluted with a pyridine-acetate buffer at pH 6.5.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:17].[C:24]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[C:11]3[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: O=C(c1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Product: CC(C)(C)c1ccc(-c2c(C(=O)c3ccccn3)cnc3c(C(F)(F)F)cccc23)cc1

Procedure:
This compound was prepared using the procedure of Example 1, step 5 using (4-chloro-8-trifluoromethyl-quinolin-3-yl)-pyridin-2-yl-methanone in place of [4-chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 4-t-butylphenylboronic acid in place of phenyl boronic acid. MS (ESI) m/z 435 ([M+H]+); Anal. Calcd for C26H21F3N2O: C, 71.88; H, 4.87; N, 6.45. Found: C, 71.51; H, 5.09; N, 6.22.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH3:11])[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=1.[CH2:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17].C(O)(=O)/C=C/C(O)=O>>[CH2:10]([O:9][CH2:8][CH2:7][N:6]1[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=[C:2]1[N:21]1[CH2:22][CH2:23][N:18]([CH2:16][CH3:17])[CH2:19][CH2:20]1)[CH3:11]
Reactant: CCOCCn1c(Cl)nc2ccccc21
Reactant: CCN1CCNCC1
Agent: O=C(O)/C=C/C(=O)O
Product: CCOCCn1c(N2CCN(CC)CC2)nc2ccccc21

Procedure:
In the same manner as described in Example 1 using 2-chloro-1-[2-(ethoxy)ethyl]benzimidazole (5.00 g), N-ethylpiperazine (5.10 g) and fumaric acid (2.91 g), there are obtained curde crystals, which are recrystallized from ethyl acetate-ethanol to give 1-[2-(ethoxy)ethyl]-2-(4-ethyl-1-piperazinyl)benzimidazole.3/2 fumarate (5.62 g) as colorless needles, m.p. 134°-135.5° C.
Reaction SMILES: [CH2:1]1[C:6]2([C:15](=[S:16])[NH:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][N:18]=[C:19]=[O:20].N12CCN(CC1)CC2>C1C=CC=CC=1>[CH3:17][NH:18][C:19]([N:14]1[C:15](=[S:16])[C:6]2([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]2)[NH:7][C:8]21[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:20]
Reactant: S=C1NC2(CCCCC2)NC12CCCCC2
Reactant: CN=C=O
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: CNC(=O)N1C(=S)C2(CCCCC2)NC12CCCCC2

Procedure:
4.8 Parts of 7,14-diazadispiro[5.1.5.2]pentadecane-15-thione, 2.28 parts of methyl isocyanate and a trace of 1,4-diazabicyclo[2.2.2]octane in 100 parts of dry benzene were heated at reflux for 4 days. A further 2.28 parts of methyl isocyanate were added and the solution again heated at reflux for 16 hours. The solvent was then evaporated in vacuo and the residue was crystallised twice from ethyl acetate to give 14-methylcarbamoyl-7,14-diazadispiro[5.1.5.2]pentadecane-15-thione as a colourless solid of melting point 127° to 129°C. This material gave the following elemental analysis by weight: