Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C@H:3]([NH:7][C:8]([C:10]1[NH:11][C:12]([C:15]2[CH:20]=[C:19]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:16]=2)=[CH:13][CH:14]=1)=[O:9])[C@@H:4]([OH:6])[CH3:5].CS(O)(=O)=O.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[CH3:36][O:35][CH2:34][C@@H:33]([O:32][C:17]1[CH:16]=[C:15]([C:12]2[NH:11][C:10]([C:8]3[O:9][CH2:2][C@@H:3]([C@@H:4]([OH:6])[CH3:5])[N:7]=3)=[CH:14][CH:13]=2)[CH:20]=[C:19]([O:21][Si:22]([CH:29]([CH3:30])[CH3:31])([CH:26]([CH3:27])[CH3:28])[CH:23]([CH3:24])[CH3:25])[CH:18]=1)[CH3:37]
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@@H](CO)[C@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C3=N[C@H]([C@H](C)O)CO3)[nH]2)c1
Reaction time: 4 h
Yield: 51.8 %

Procedure:
N-[(2S,3S)-1,3-Dihydroxybutan-2-yl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tripropan-2-ylsilyl)oxy]phenyl)-1H-pyrrole-2-carboxamide (1.76 g, 3.29 mmol) synthesized in Example (112a) was dissolved in tetrahydrofuran (20 mL), and anhydrous methanesulfonic acid (0.54 g, 3.10 mmol) and triethylamine (1.00 mL, 7.17 mmol) were added at −40° C., followed by stirring at the same temperature for 4 hours under nitrogen atmosphere, and then at 50° C. overnight. To the reaction solution, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=2%-5%) to afford the desired compound (880 mg, yield 52%) as a white foam.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12](=O)[CH2:13][C:14](=O)/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]4[CH2:29][CH2:28][CH2:27][O:26]4)=[CH:19][C:18]=3[O:30][CH3:31])[CH:8]=2)[CH:3]=[CH:2]1.O.[NH2:35][NH2:36]>C(O)(=O)C.C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14](/[CH:15]=[CH:16]/[C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]5[CH2:29][CH2:28][CH2:27][O:26]5)=[CH:19][C:18]=4[O:30][CH3:31])[NH:36][N:35]=3)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: COc1cc(OCC2CCCO2)ccc1/C=C/C(=O)CC(=O)/C=C/c1ccc2cc[nH]c2c1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(OCC2CCCO2)ccc1/C=C/c1cc(/C=C/c2ccc3cc[nH]c3c2)n[nH]1
Temperature: 60 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
In 4.5 mL of acetic acid was dissolved 400 mg (0.898 mmol) of (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-tetrahydrofuranylmethoxy)phenyl]hepta-1,6-diene-3,5-dione. To this solution was added 0.45 g (9.0 mmol) of hydrazine monohydrate at room temperature and the mixture was stirred at 60° C. for 3 hours. The resulting reaction mixture was diluted with ethyl acetate, washed with a saturated sodium bicarbonate aqueous solution and then with saturated brine, and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate or methylene chloride/methanol). The resulting solid was washed with an organic solvent to give 298 mg (75% yield) of the title compound as a pale yellowish white powder with the following properties.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br.Cl>CC(N(C)C)=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[C:39]([F:40])[C:32]=3[F:31])[C:8]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Fc1cccc(CBr)c1F
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2cccc(F)c2F)c1=O
Reaction time: 8 h
Yield: 32 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 2,3-difluorobenzyl bromide (255 uL, 2.0 mmoles) in dimethylacetamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from ethanol-water gave the title compound (140 mg, 32%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s., 1 H), 10.11 (br. s., 1 H), 7.25-7.43 (m, 1 H), 7.08-7.23 (m, 1 H), 7.03 (t, J=7.07 Hz, 1 H), 5.08 (s, 2 H), 4.55-4.73 (m, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 2.12-2.35 (m, 2 H), 1.78 (d, J=12.63 Hz, 2 H), 1.63 (s, 3 H), 1.20-1.38 (m, 2 H), 1.02-1.18 (m, 1 H)
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](=O)[NH:13][C:12]([CH2:19][O:20][CH3:21])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O.CN(C)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:24])=[N:13][C:12]([CH2:19][O:20][CH3:21])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1nc2c(c(=O)[nH]1)CCN(Cc1ccccc1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)c1ccccc1
Product: COCc1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Temperature: 80 °C
Yield: 82.3 %

Procedure:
A mixture of 7-benzyl-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4(3H)-one (2.01 g, 7.04 mmol), phosphorus oxychloride (5.16 mL, 56.35 mmol) and N,N-dimethylaniline (0.89 mL, 7.04 mmol) in 1,2-dichloroethane was heated to 80° C. for two h. The mixture was allowed to cool to r.t. and poured over crushed ice (100 mL). The mixture was made basic (pH=˜8) by the addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (200 mL). The organic layer was dried over magnesium sulfate and concentrated to leave a dark oil which was purified by silica gel chromatography (ethyl acetate/hexane gradient) to yield 1.76 g (82%) of the title compound as a brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[Br:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42]([S:47]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)(=[O:49])=[O:48])[CH:41]=[CH:40]2>CN(C=O)C.C(OCC)(=O)C>[Br:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42]([S:47]([N:50]1[CH2:51][CH2:52][N:53]([C:11](=[O:13])[C:10]3[CH:9]=[CH:8][C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[CH:15][CH:14]=3)[CH2:54][CH2:55]1)(=[O:48])=[O:49])[CH:41]=[CH:40]2
Reactant: O=S(=O)(c1ccc2cc(Br)ccc2c1)N1CCNCC1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(-c2ccncc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14 %

Procedure:
4-(4-Pyridyl)benzoic acid (238 mg,1.2 mmol) was suspended in DMF (5 mL) with triethylamine (0.17 mL, 1.2 mmol). The reaction mixture was stirred at room temperature for 15 minutes then cooled to 5° C. Carbonyldiimidazole (194 mg, 1.2 mmol) was added and the reaction mixture allowed to warm slowly to room temperature over one hour. 4-(6-Bromonaphth-2-ylsulphonyl)piperazine hydrochloride (470 mg, 1.2 mmol) was added as a solid in one portion and the reaction mixture stirred for 2 days at room temperature. The reaction mixture was diluted with ethyl acetate (50 mL) and washed twice with saturated aqueous sodium hydrogen carbonate solution (2×50 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting solid was subjected to chromatography (SiO2; 2%, 4%, 6%. 8%, 10% methanol/ethyl acetate) to yield 1-(6-bromonaphth-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine as a white solid (90 mg), 1H NMR (DMSO-d6) δ=3.07 ppm (s,4H), δ=3.59 ppm (s,4H), δ=7.27 & 7.46 ppm (dd,4H), δ=7.18 & 8.64 ppm (dd,4H), δ=7.34 ppm (m,2H), δ=8.17 ppm (dd,2H), δ=8.39 ppm (d,1H), δ=8.47 ppm (s,1H); MS (M+H)+ 536.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([Cl:8])=[CH:6][N:5]([CH3:9])[N:4]=1.[CH3:10][C:11]1[N:16]=[C:15]([SH:17])[N:14]=[C:13]([OH:18])[CH:12]=1.C(N(CC)CC)C>C(O)C>[Cl:8][C:7]1[C:3]([CH2:2][S:17][C:15]2[N:14]=[C:13]([OH:18])[CH:12]=[C:11]([CH3:10])[N:16]=2)=[N:4][N:5]([CH3:9])[CH:6]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cn1cc(Cl)c(CBr)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2nn(C)cc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 3-(bromomethyl)-4-chloro-1-methyl-1H-pyrazole (61.7 mmol) in absolute ethanol (250 mL) was added 6-methyl-2-sulfanylpyrimidin-4-ol (5.84 g, 41.1 mmol) and triethylamine (23.0 mL, 165 mmol) at 0° C. The mixture was stirred at room temperature overnight. The white solid was filtered and washed with diethyl ether (300-500 mL). The filtrate was recovered, and the solvent was evaporated. The residue triturated in water, filtered, and washed with water (3×300 mL) and then DCM (50 mL). The solid was died under vacuum overnight. 2-{[(4-chloro-1-methyl-1H-pyrazol-3-yl)methyl)sulfanyl}-6-methylpyrimidin-4-ol was obtained as a white solid (5.48 g, 49% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (bs, 3H), 3.78 (s, 3H), 4.35 (s, 2H), 6.05 (bs, 1H), 7.92 (s, 1H); LRMS (ES+) m/z 271 (100%, M+1); 273 (35%, M+3).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH2:13]I)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:25]=1)[N:22]=[CH:21][CH:20]=[CH:19]2>>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH2:13][N:29]3[CH2:30][CH2:31][N:26]([C:24]4[CH:25]=[C:16]([Cl:15])[CH:17]=[C:18]5[C:23]=4[N:22]=[CH:21][CH:20]=[CH:19]5)[CH2:27][CH2:28]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[ClH:15]
Reactant: Clc1cc(N2CCNCC2)c2ncccc2c1
Reactant: COc1cccc2c(CCI)coc12
Product: COc1cccc2c(CCN3CCN(c4cc(Cl)cc5cccnc45)CC3)coc12
Product: Cl

Procedure:
8-{4-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloro-quinoline was prepared by generally following the procedure outlined in example 18, step 3, starting from 2-(7-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-chloro-8-piperazino quinoline (247 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate. A HCl salt was prepared, yielding a green spongy solid. mp 248° C.; Yield: 320 mg (69%); (M+H): 424; 1H NMR δ 11.8 (bs, 1H), 9.0 (d, 1H), 8.5 (d, 1H), 8.0 (s, 1H), 7.8-7.0 (m, 5H), 6.8 (d, 1H), 4.2 (d, 2H), 3.9 (s, 3H), 3.7-3.2 (m, 10H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][C:17]1[CH:18]=[C:19]([NH:28][C:29]([NH2:31])=[S:30])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:32](I)[CH3:33]>CC(C)=O>[C:12]([O:11][C:9]([N:8]([CH2:16][C:17]1[CH:18]=[C:19]([NH:28][C:29](=[NH:31])[S:30][CH2:32][CH3:33])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27]1)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N(Cc1cc(NC(N)=S)ccc1-n1cccc1)C(=O)OC(C)(C)C
Solvent: CC(C)=O
Product: CCSC(=N)Nc1ccc(-n2cccc2)c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Yield: 77 %

Procedure:
A mixture of the compound (55 mg) obtained in Example 1f, ethyl iodide (0.039 ml) and acetone (5 ml) was heated under reflux for 14 hours and then concentrated at reduced pressure. Saturated sodium hydrogencarbonate solution was added to the resulting residue and extraction with ethyl acetate was conducted. The organic layer was washed with brine, dried with anhydrous sodium sulfate and then concentrated at reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=4:6) to give the titled compound (yield, 77%).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[C:13]([OH:23])(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.C(N(CC)CC)C.[NH2:31][CH2:32][CH2:33][NH:34][C:35]1[C:44]([C:45]#[N:46])=[CH:43][C:42]2[C:37](=[CH:38][C:39]([CH3:48])=[CH:40][C:41]=2[CH3:47])[N:36]=1>C(Cl)Cl>[C:45]([C:44]1[C:35]([NH:34][CH2:33][CH2:32][NH:31][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[N:36][C:37]2[C:42]([CH:43]=1)=[C:41]([CH3:47])[CH:40]=[C:39]([CH3:48])[CH:38]=2)#[N:46]
Reactant: COc1cccc(C(=O)O)c1
Reactant: Cc1cc(C)c2cc(C#N)c(NCCN)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)NCCNc2nc3cc(C)cc(C)c3cc2C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
EDC hydrochloride (0.192 g, 1 mmol), m-anisic acid (0.152 g, 1 mmol) and triethylamine (0.14 mL, 2.5 mmol) were dissolved in dry DCM (10 mL). The reaction was stirred at room temperature for 30 min. Carbonitrile 4 (0.201 g, 1 mmol) dissolved in 5 mL dry DCM was added dropwise to the solution and reaction stirred for 18 h. The reaction was diluted with DCM (50 mL) and washed with 1M NaHSO4 (aq, 2×100 mL). Organics were dried over Na2SO4, filtered and solvent was removed under reduced pressure. The crude product was then purified by flash chromatography (4:1 hexane:ethyl acetate mobile phase) to produce a light yellow solid (Compound 22) in 73% yield. 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.13 (s, 1H), 7.32 (s, 1H), 7.28 (s, 1H), 7.20 (d, J=7.5, 1H), 7.13 (t, J=7.8, 1H), 6.98 (s, 1H), 6.95 (d, J=8.1, 1H), 5.82 (s, 1H), 3.91 (q, J=5.3, 2H), 3.79-3.68 (m, 5H), 2.55 (s, 3H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.10, 159.87, 155.10, 144.27, 140.97, 136.27, 135.41, 129.42, 127.13, 124.48, 119.35, 119.23, 117.72, 116.87, 112.46, 94.30, 55.49, 43.39, 41.25, 29.92, 22.21, 18.57. IR (neat): 3380, 3357, 2957, 2925, 2217, 1605, 1583, 1535, 1258. ESI-LCMS m/z [M+H]+=375.18.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:17]([N:19](CC)[CH2:20][CH3:21])[CH3:18].C(Cl)(=O)C(C)(C)C.N1CCCC1.Cl>C(OCC)(=O)C>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:19]1[CH2:20][CH2:21][CH2:18][CH2:17]1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN(CC)CC
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N)C(=O)O
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
3.46 g (15 mmoles) of BOC-Leu-OH are dissolved in 50 ml of ethyl acetate, 2.1 ml (15 mmoles) of triethylamine are added, and the mixture is cooled to -15° C. 1.97 ml (16 mmoles) of pivaloyl chloride are added dropwise to the stirred mixture at such a rate that the temperature remains below -10° C., the resulting suspension is stirred for 10 minutes, and then 1.37 ml (16.5 mmoles) of pyrrolidine are added dropwise to the suspension at the same temperature. When the addition is complete, the mixture is stirred at -10° C. for additional 30 minutes, and then allowed to stand at 5° C. for 3 hours. The reaction mixture is shaken thrice with 10 ml of n hydrochloric acid, each, thrice with 10 ml of n sodium hydrocarbonate solution, each, and then with 10 ml of water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The oily residue is dissolved in 5 ml of ethyl acetate, and 10 ml of a 5 n hydrochloric acid solution in ethyl acetate are added. After one hour of standing the solution is diluted with ether and extracted with water. The aqueous solution is washed with ether, rendered alkaline with potassium carbonate, and then extracted with chloroform. The chloroform solution is dried over anhydrous sodium sulfate, evaporated, the oily residue is dissolved in 10 ml of ether, and the pH of the solution is adjusted to 3 with a concentrated solution of hydrochloric acid in ethyl acetate. The separated crystals are filtered off to obtain 2.41 g (73%) of H-Leu-pyrrolidine.HCl; m.p.: 170°-174° C. (decomposition), Rf5 =0.37.
Reaction SMILES: [OH-].[Na+:2].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([OH:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9]>O.CC(O)C>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([O-:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9].[Na+:2]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Yield: 110.4 %

Procedure:
A solution of sodium hydroxide (0.63 g) in water:IPA (80:20 v/v, 38 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water:IPA (80:20 v/v, 212 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 45 minutes. Then the reaction mixture was cooled to room temperature. The clear solution was evaporated until dry to give 5.9 g of amorphous ibandronate sodium.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[CH3:2].S(Cl)([Cl:15])(=O)=O.C([O-])(O)=O.[Na+]>CCOCC>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([Cl:15])[C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCCC(=O)C(Cl)C(=O)OCC
Temperature: 0 °C
Yield: 99.4 %

Procedure:
3-oxo-hexanoic acid ethyl ester (29.7 g, 188 mmol) was dissolved in Et2O (400 ml). The solution was cooled to 0° C., and sulfuryl chloride (22.6 ml, 282 mmol) was added dropwise. The solution gradually warmed to RT over 4 h. The solution was neutralized to pH 7 with a solution of aqueous saturated NaHCO3. The organic layer was separated, washed with brine, and dried over sodium sulfate. Evaporation under reduced pressure yielded 2-chloro-3-oxo-hexanoic acid ethyl ester (intermediate Id, 36 g, 100%). 1H-NMR (CDCl3, ppm): 0.95 d (3H); 1.35 d (3H); 1.58 m (2H); 2.7 t (2H); 4.28(d (2H); 4.78 s (1H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1.[Cu][C:17]#[N:18].ClCCl>CN(C=O)C>[C:17]([C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1)#[N:18]
Reactant: O=C1Nc2ccc(Br)cc2C2CCCC12
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)C1CCCC1C(=O)N2
Yield: 38.3 %

Procedure:
A solution of 8-bromo-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (230 mg, 0.86 mmol) in DMF (20 ml) is mixed with copper(I) cyanide (77 mg, 0.86 mmol) and refluxed for 16 hours. The batch is diluted dichloromethane, washed with saturated NH4Cl, dried (Na2SO4) and concentrated by evaporation in a vacuum. Purification on silica gel with ethyl acetate-hexane yields 70 mg (38%) of product.
Reaction SMILES: C1(COC2C(C3N(CC4C=CC(CCC(O)=O)=CC=4)C4C=C(F)C(F)=CC=4N=3)=CC=CN=2)CC1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:46]([CH2:47][CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)[C:45]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=3[N:43]=2)=[C:38]([O:60][CH2:61]C2C=CC=CC=2Cl)[CH:37]=1.BrCC1C=CC=CC=1>>[CH2:47]([N:46]1[C:45]2[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=2[N:43]=[C:42]1[C:39]1[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][C:38]=1[O:60][CH3:61])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3OCc3ccccc3Cl)n(CC3CCCCC3)c2cc1F
Agent: BrCc1ccccc1
Agent: O=C(O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Product: COc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1ccccc1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and bromomethyl-benzene (CAS Reg. No. 100-39-0). Brown sticky solid (81%). MS (Turbo Spray): m/z=385.2 (M+H).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[S:5])#[N:2].[Na].C([C:10](O)=[CH:11][C:12](=O)[CH3:13])C.[C:16](O)(=O)C.N1CCCCC1>O.C(O)(=O)C>[CH3:13][C:12]1[C:11]([CH3:10])=[N:6][C:4]([SH:5])=[C:3]([CH:16]=1)[C:1]#[N:2]
Reactant: N#CCC(N)=S
Reactant: CCC(O)=CC(C)=O
Reactant: CC(=O)O
Agent: [Na]
Solvent: C1CCNCC1
Solvent: O
Product: Cc1cc(C#N)c(S)nc1C

Procedure:
A mixture of cyanothioacetamide (2.0 g, 20 mmol), the sodium salt of ethyl-3-oxo-butenol (2.44 g, 20 mmol) and piperidine acetate (1.9 ml) in water (20 ml) is heated at reflux before adding acetic acid (3 ml). The resulting precipitate is filtered and washed with water. The crude product is dissolved by heating in methanol. Filtering and evaporation of the solvent under reduced pressure yields 5,6-dimethyl-2-mercapto-nicotine nitrile.
Reaction SMILES: C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[NH:22][CH:23]=1.[N:25]1[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27][CH:26]=1.C(Cl)(Cl)Cl.C(O)C>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[N:22]([CH2:31][C:28]2[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=2)[CH:23]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: OCc1ccncc1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: O=c1ncc(Cl)cn1Cc1ccncc1
Temperature: 90 °C
Yield: 23.7 %

Procedure:
N,N-Dimethylformamide dineopentyl acetal (1.8 ml) was added to a stirred suspension of 5-chloropyrimidin-2-one (522 mg) and 4-pyridylcarbinol (611 mg) in dry N,N-dimethylformamide (10 ml) under nitrogen and the the mixture was then heated at 90° C. After 41/2 h the reaction mixture was evaporated to a brown solid which was subjected to column chromatography on silica developing and eluting with chloroform-ethanol, 14:1. This gave a yellow crystalline solid which was subjected to p.l.c. on silica developing with chloroform-ethanol, 9:1 (three runs). The major band was eluted with chloroform-ethanol, 1:1, to give a pale yellow foam which was crystallised from acetone to give off white crystals of the title pyrimidinone (210 mg), m.p. 205°-206° C., λmax (EtOH) 246 nm (ε 7.050), 332.5 nm (ε 950).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1)=O.[NH3:16]>>[OH:15][C:14]1[C:5]([C:3]([NH2:16])=[O:2])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: COC(=O)c1ccc2cccnc2c1O
Reactant: N
Product: NC(=O)c1ccc2cccnc2c1O

Procedure:
8-Hydroxy-7-quinolinecarboxylic acid methyl ester [as reported by Eckstein, Z. et al. in Pol. J. Chem. 1979, 53(11), 2373-7 (C.A. 92, 215243s)] is reacted with excess ammonia in a steel bomb for 12-18 hr. The excess ammonia is allowed to evaporate and the residue is crystallized from a suitable solvent to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[S:6][C@@H:5]2[C@H:7]([NH2:10])[C:8](=[O:9])[N:4]2[C@H:3]1[C:11]([OH:13])=[O:12].C[O:16][C:17]([C@H:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O.Cl>>[CH3:1][C:2]1([CH3:14])[S:6][C@@H:5]2[C@H:7]([NH:10][C:17]([C@H:19]([NH2:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:16])[C:8](=[O:9])[N:4]2[C@H:3]1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)[C@H](N)c1ccccc1
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Agent: Cl
Product: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O

Procedure:
Under the condition similar to that of Example 15, 6-aminopenicillanic acid is reacted with D-α-phenylglycine methyl ester hydrochloride using the mycelium obtained in the procedure of Example 15 to produce 0.08 g of Ampicillin when determined by microbiological assay.