Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:18][C:19](=[O:27])[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9][NH:10]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[S:34](Cl)([C:37]1[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=1)(=[O:36])=[O:35]>C(Cl)Cl.O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:9][NH:10][S:34]([C:37]2[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:18][C:19]([NH:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:27])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(CC(=O)Nc1ccccc1)c1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCC(CC(=O)Nc2ccccc2)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 34 (0.106 g, 0.271 mmol) in DCM (2 ml) TFA (2 ml) was added. After stirring for 2 h at room temperature, the solvent was distilled under reduced pressure to give a brown solid. The crude residue was dissolved as obtained in 1,4-dioxane:H2O 1:1 (5 ml) and K2CO3 (0.225 g, 1.63 mmol, 6 eq) was added followed by tosyl chloride (0.056 g, 0.298 mmol, 1.1 eq) at room temperature. After stirring for 2 h at room temperature, the resulting mixture was evaporated in vacuo to dryness. Water (10 ml) was added and the resulting white solid was separated by filtration and dried. Pure 36 was obtained without further purification (0.079 g, 0.179 mmol, 66%), mp 200-202° C. 1H NMR (400 MHz, CD3OD) δ 2.39 (3H, s, Ar—CH3), 2.56 (1H, dd, J 9.2, 14.4 Hz, H—CHCO), 2.77 (1H, dd, J 6.8, 14.4 Hz, H—CHCO), 3.06 (1H, dd, J 8.2, 13.0 Hz, H—CHNH), 3.15 (1H, dd, J 6.8, 13.2 Hz, H—CHNH) 7.03-7.07 (1H, m, CH, Ar), 7.15 (2H, d, J 8.4 Hz, 2×CH, Ar), 7.21-7.26 (4H, s, 4×CH, Ar), 7.29 (2H, d, J 8.0 Hz, 2×CH, Ar), 7.36-7.38 (2H, m, 2×CH, Ar), 7.62 (2H, d, J 8.8 Hz, 2×CH, Ar). 13C NMR (400 MHz, DMSO-d6) δ21.63 (s) (Ar—CH3), 40.73 (s) (CH2CO), 41.87 (s) (CH2CHCH2), 48.13 (s) (CH2NH), 119.79 (s) (2×CH, Ar), 123.80 (s) (CH, Ar), 127.14 (s) (2×CH, Ar), 128.80 (s) (2×CH, Ar), 129.29 (s) (2×CH, Ar), 130.23 (s) (2×CH, Ar), 130.36 (s) (2×CH, Ar), 131.80 (s) (C, Ar), 138.14 (s) (C, Ar), 139.64 (s) (C, Ar), 141.53 (s) (C, Ar), 143.20 (s) (C, Ar), 169.81 (s) (C═O). νmax (pure sample)/(cm−1) 3340 (md) (N—H), 3141 (md) (N—H), 1665 (st) (C═O), 1598 (st), 1547 (st), 1493 (md), 1444 (st), 1154 (st), 1087 (md). MS (API-ES): m/z 443 [M+H]+ (100%), HRMS (API-ES) m/z found 443.1201 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:20])CC>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([F:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(F)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A −70° C. solution of (R)-(−)-3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (5 g, 26.7 mmol) in anhydrous EtOAc (250 mL) was treated dropwise with DAST (4.6 mL, 1.3 equiv.) and stirred for 1.5 h. The reaction was allowed to warm to room temperature over a period of 3 h. The reaction mixture was poured into ice cold saturated aqueous sodium bicarbonate solution (300 mL). The EtOAc layer was separated and washed with additional saturated aqueous sodium bicarbonate solution (2×300 mL) and then with brine (300 mL). The organics were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The crude residue was purified by silica gel chromatography (Hexanes to 1:9 EtOAc:Hexanes, gradient eluant) to yield 3-Fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester as an oil (1.7 g).
Reaction SMILES: [CH2:1]([C:4]([CH2:9][CH2:10][CH3:11])([CH2:7][OH:8])[CH2:5][OH:6])[CH2:2][CH3:3].[CH3:12]I>>[CH2:9]([C:4]([CH2:1][CH2:2][CH3:3])([CH2:5][O:6][CH3:12])[CH2:7][OH:8])[CH2:10][CH3:11]
Reactant: CCCC(CO)(CO)CCC
Reactant: CI
Product: CCCC(CO)(CCC)COC

Procedure:
2,2-Di-n-propyl-3-methoxy-1-propanol was prepared from 2,2-di-n-propyl-1,3-propandiol and methyl iodide through the same procedure as described above.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13]>>[Cl:3][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13]
Reactant: O=C1CCCN1CCO
Reactant: O=S(Cl)Cl
Product: O=C1CCCN1CCCl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Add thionyl chloride (5 mL) to 1-(2-hydroxy-ethyl)-pyrrolidin-2-one (1.12 mL, 10.0 mmol) dropwise then stir at room temperature for 10 min. Remove solvent in vacuo to give the title compound as an orange oil. MS (ES+) m/z: 148 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([C:21]3[C:26]([F:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:29]([OH:31])=O)[CH2:12]1)(=[O:10])=[O:9].[CH2:32]([NH:36][C:37](=[O:44])[C:38](=[O:43])[C@@H:39]([NH2:42])[CH2:40][CH3:41])[CH2:33][CH2:34][CH3:35]>>[CH2:32]([NH:36][C:37](=[O:44])[C:38](=[O:43])[C@@H:39]([NH:42][C:29]([C@@H:13]1[CH2:12][C@@H:11]([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])[CH2:15][N:14]1[C:16]([C:18]1([C:21]2[C:26]([F:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=2)[CH2:19][CH2:20]1)=[O:17])=[O:31])[CH2:40][CH3:41])[CH2:33][CH2:34][CH3:35]
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1
Reactant: CCCCNC(=O)C(=O)[C@@H](N)CC
Product: CCCCNC(=O)C(=O)[C@H](CC)NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-4-(2-Chloro-benzenesulfonyl)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid and (S)-3-Amino-2-oxo-pentanoic acid butylamide in step 1. MS (m/e)=655.15 [M+H+].
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([F:17])[F:16])[CH2:10][CH2:9]1)(C)(C)C.[ClH:19]>O1CCOCC1>[ClH:19].[ClH:19].[F:17][CH:15]([F:16])[CH2:14][N:11]1[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(CC(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0 degrees) mixture of 1.21 g (4.58 mmole) of [1-(2,2-difluoro-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and 20 mL of dioxane, was added 5.7 mL of 4M HCl in dioxane. The mixture was stirred at room temperature overnight, and the solid collected by filtration to give 0.90 g of 1-(2,2-difluoro-ethyl)-piperidin-4-ylamine dihydrochloride.
Reaction SMILES: [CH2:1]([S:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)[CH2:2][CH3:3].C([Li])CCC.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.CCCCCC>[C:16]1([S:22]([N:9]2[CH:5]([S:4][CH2:1][CH2:2][CH3:3])[CH2:6][CH2:7][C:8]2=[O:10])(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCSC1CCC(=O)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCSC1CCC(=O)N1S(=O)(=O)c1ccccc1
Yield: 34.7 %

Procedure:
To 2.3 g of 5-propylthio-pyrrolidin-2-one in solution in 120 cm3 of tetrahydrofuran, there is added at -70° C./-65° C., 9.6 cm3 of a 1.5M solution of butyllithium in hexane. After 20 minutes at this temperature, 2.55 g of benzenesulphonyl chloride is added in 20 cm3 of tetrahydrofuran. After allowing to return slowly to ambient temperature, concentrating and chromatographing on silica (eluent: hexane-ethyl acetate, 3-7), 1.5 g of the expected product is obtained. m.p. 49°-51° C. crystallized from isopropyl ether.
Reaction SMILES: [N:1]1([C:6]([N:8]2[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@H:10]([O:25][CH3:26])[CH2:9]2)=[S:7])C=CN=C1.N.CO>C1COCC1.[Cl-].[Na+].O>[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:10]([O:25][CH3:26])[CH2:9]1)(=[S:7])[NH2:1]
Reactant: CO[C@@H]1CN(C(=S)n2ccnc2)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CO[C@@H]1CN(C(N)=S)CC[C@@H]1NC(=O)OCc1ccccc1
Reaction time: 42 h
Yield: 67.4 %

Procedure:
Benzyl cis(±)-[1-(1H-imidazol-1-ylthiocarbonyl)-3-methoxypiperidin-4-yl]-carbamate obtained in Example (64a) (about 1.36 mmol) was dissolved in THF (2 mL). A 2 N ammonia/methanol solution (10 mL) was added, and the mixture was stirred for 42 hours. Brine was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The precipitated solid was collected by filtration to obtain 296.5 mg of the title compound as a white solid (67%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH2:31]([NH2:34])[CH2:32][CH3:33]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[C:15]2[O:14][CH:13]([CH2:12][NH:34][CH2:31][CH2:32][CH3:33])[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Reactant: CCCN
Product: CCCNCC1Cc2cc(Cl)cc(-c3c(C)cccc3C)c2O1

Procedure:
The title compound was prepared (0.094 g, 76%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and propylamine (0.40 g, 6.76 mmol) mp 200-202° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3[C:15]([C:6]=2[CH:5]=[CH:4][C:3]=1[O:20]CC1C=CC(OC)=CC=1)=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[N:12][CH:11]=3.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>ClCCl>[F:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3[C:15]([C:6]=2[CH:5]=[CH:4][C:3]=1[OH:20])=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[N:12][CH:11]=3.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]
Reactant: COc1ccc(COc2ccc3c(c2F)OCc2cnc(NC(C)=O)cc2-3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc2c(cn1)COc1c-2ccc(O)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-(7-fluoro-8-((4-methoxybenzyl)oxy)-5H-chromeno[3,4-c]pyridin-2-yl)acetamide (150 mg, 0.380 mmol) in dichloromethane (5 mL) was added TFA (0.059 mL, 0.761 mmol) at room temperature and the reaction mixture was stirred at rt for 2 h. After the completion of reaction the volatiles were removed under reduced pressure. The residue was washed with diethyl ether (7 mL) and stirred for 5 min. The solid was collected by vacuum filtration and dried under vacuum to yield N-(7-fluoro-8-hydroxy-5H-chromeno[3,4-c]pyridin-2-yl)acetamide, TFA (70 mg, 0.170 mmol, 45% yield) as a white solid. LCMS (ESI) m/e 275.0 [(M+H)+, calcd for C14H12FN2O3 275.1]; LC/MS retention time (Method E): tR=2.0 min.
Reaction SMILES: CO[C:3](=[O:18])[C:4]([C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH2:10][CH2:9][N:8]3[CH:7]=1)=O.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][C:29]([NH2:31])=[S:30])=[CH:20]1.C(O[K])(C)(C)C.Cl>C1COCC1.CCOC(C)=O.O>[C:6]1([C:4]2[C:3](=[O:18])[NH:31][C:29](=[S:30])[C:28]=2[C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][CH:20]=2)[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH2:10][CH2:9][N:8]3[CH:7]=1
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2
Reactant: NC(=S)Cc1c[nH]c2ccccc12
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1NC(=S)C(c2c[nH]c3ccccc23)=C1c1cn2c3c(cccc13)CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-oxo-acetic acid methyl ester (3.4 g, 14 mmol) and 2-(1H-indol-3-yl)-thioacetamide (2.9 g, 15 mmol) in anhydrous THF (34 mL) at −30° C. under N2 was added dropwise 1M tBuOK in THF (42 mL, 42 mmol). The reaction mixture was allowed warm to room temperature over 2 h. The reaction mixture was cooled to 0° C. and concentrated HCl (42 mL) added slowly. The mixture was allowed warm to room temperature with stirring over 1 h before being diluted with EtOAc and water. The organics were separated, washed with brine and evaporated to yield a dark residue. The residue was purified by column chromatography (SiO2, EtOAc/hexanes). 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-5-thioxo-1,5-dihydro-pyrrol-2-one was obtained as a dark foam (4.7 g, 87%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:43])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH2:41][CH3:42])=[CH:39][CH:40]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:41]([C:38]1[N:37]=[CH:36][C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:43])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:23])([F:21])[F:22])[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)=[CH:40][CH:39]=1)[CH3:42]
Reactant: CCc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from [2-{3-[3-(6-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M175) (387 mg, 0.619 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (191 mg, 61%).
Reaction SMILES: [BrH:1].[C:2]([C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([C:21](=[O:23])[CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C@H:13]([CH2:14][C@@H:15]2[O:24][C@@H:16]2[CH2:17]1)[CH2:12][CH2:11]3)#[N:3]>C(Cl)(Cl)Cl>[Br:1][C@H:16]1[CH2:17][C@@:18]2([CH3:19])[C@@H:13]([CH2:12][CH2:11][C@@H:10]3[C@@H:20]2[C:21](=[O:23])[CH2:22][C@@:5]2([CH3:6])[C@H:7]3[CH2:8][CH2:9][C@@H:4]2[C:2]#[N:3])[CH2:14][C@@H:15]1[OH:24]
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C#N)[C@@]3(C)CC(=O)[C@@H]12
Reactant: Br
Solvent: ClC(Cl)Cl
Product: C[C@]12C[C@H](Br)[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C#N)[C@@]3(C)CC(=O)[C@@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aqueous 48% hydrobromic acid (60 ml.) was added to a solution of 17β-cyano-2α,3α-epoxy-5α-androstan-11-one (3.03g.) in chloroform (175ml.) and the mixture stirred at room temperature for 1 hr. The organic phase was separated, washed with aqueous 10% sodium bicarbonate and water and dried. Filtration and evaporation followed by preparative t.l.c. afforded the pure title compound as a white froth (2.16g.); [α]D + 68.5°, (c 0.6).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[C:11]([O:15][CH2:16][CH2:17][NH2:18])([CH3:14])([CH3:13])[CH3:12]>>[NH2:1][C:2]1[CH:9]=[C:8]([NH:18][CH2:17][CH2:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: CC(C)(C)OCCN
Reactant: N#Cc1cnc(N)cc1F
Product: CC(C)(C)OCCNc1cc(N)ncc1C#N

Procedure:
From intermediate 21 and 2-(tert-butoxy)ethanamine, reacted in an analogous manner to the preparation of intermediate 102. (UPLC-MS 3) Rt=0.58 min; MS m/z [M+H]+ 235.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].C(N(CC)CC)C.[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>C(Cl)(Cl)Cl.C(Cl)Cl>[C:4]([CH2:3][NH:2][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[Cl:13])#[N:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: N#CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: N#CCNC(=O)c1ccccc1Cl

Procedure:
To a stirred mixture of 9.3 g (0.1 mole) aminoacetonitrile hydrochloride and 20.2 g (0.2 moles) triethylamine in 200 ml chloroform, 17.5 g (0.1 mole) o-chlorobenzoyl chloride in 25 ml methylene chloride were dropped in over 30 minutes in a moderately exothermic addition. The reaction mixture was washed twice with 75 ml water. On the second washing, solids separated which were filtered and washed well with water. Beige solids were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:29][CH:30]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][C:6]1[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=[C:2]([NH:34][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=2)(=[O:32])=[O:33])[N:7]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CCCC(C(=O)OC)c1c(C)nc(NS(=O)(=O)c2ccc(C)cc2)nc1-c1ccc(C)cc1
Yield: 22.8 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.300 mmol), p-toluenesulfonamide (0.061 mg; 0.361 mmol), palladium acetate (2 mg, 0.009 mmol) and xantphos (10 mg; 0.018 mmol) were placed in a 2 mL reaction tube and dissolved in dioxane (1 mL), the tube was purged with argon, sealed and irradiated in a microwave oven at 160° C. for 30 min. The reaction mixture was partitioned between a saturated sodium chloride solution and dichloromethane, filtered over a phase separator filter (1PS) and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (10-80%) in heptane to yield 32 mg (22%) of the title compound as a colorless oil.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.F[C:14]1[N:15](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:16]=[CH:17][N:18]=1.FC1NC=CN=1.[NH2:44][CH:45]1[C:62](=[O:63])[N:47]2[C:48]([C:59]([OH:61])=[O:60])=[C:49]([CH2:52][S:53][C:54]3[S:55][CH:56]=[N:57][N:58]=3)[CH2:50][S:51][C@H:46]12>CN(C=O)C>[NH:15]1[CH:16]=[CH:17][N:18]=[C:14]1[NH:44][CH:45]1[C:62](=[O:63])[N:47]2[C:48]([C:59]([OH:61])=[O:60])=[C:49]([CH2:52][S:53][C:54]3[S:55][CH:56]=[N:57][N:58]=3)[CH2:50][S:51][C@H:46]12
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Reactant: Fc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Fc1ncc[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C1=C(CSc2nncs2)CS[C@@H]2C(Nc3ncc[nH]3)C(=O)N12
Reaction time: 0.08 h
Yield: 11.4 %

Procedure:
To a solution of toluene-p-sulphonic acid hydrate (54 mg.) in dry DMF (1 ml.) was added 2-fluoro-1-triphenylmethylimidazole (110 mg.) and the solution heated in a preheated bath at 80°. After 5 minutes, to allow complete formation in situ of 2-fluoroimidazole, 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethylceph-3-em-4-carboxylic acid (110 mg.) was added and heating continued for 2.5 hours. A further portion of the fluoroimidazole (50 mg.) was then added, heating was continued for a further 30 minutes, and the mixture was cooled and evaporated at room temperature. To the residue was added water (10 ml.) and ethyl acetate (25 ml.) and the mixture filtered and the phases separated. The aqueous layer was concentrated to 4 ml., filtered and subjected to preparative HPLC on Whatman "Partisil 10" using water/MeOH/HOAc 80:20:1 v/v/v as eluant. The product crystallised on addition of acetone. It was washed with acetone and ether to give 7-(imidazol-2-yl)amino-3-(1,3,4-thiadiazol-2-yl)thiomethylceph-3-em-4-carboxylic acid (15 mg.) having the following n.m.r. in d6DMSO+CD3COOD: 3.52 (d, 1H); 3.79 (d, 1H); 4.33 (d, 1H); 4.6 (d, 1H); 5.12 (d, 1H); 5.58 (d, 1H); 6.83 (s, 2H); 9.49 (s, 1H).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]#[C:23][CH:24]2[CH2:26][CH2:25]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CN(C)C=O.[Cu]I>[Si:1]([O:8][CH:9]1[CH2:10][CH2:11][CH:12]([N:15]2[C:16]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:22]=[C:23]2[CH:24]2[CH2:25][CH2:26]2)[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(Nc2ccccc2C#CC2CC2)CC1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCC(n2c(C3CC3)cc3ccccc32)CC1
Temperature: 25 °C

Procedure:
To a solution of [4-(tert-butyldimethylsilanyloxy)cyclohexyl]-(2-cyclopropylethynylphenyl)amine (3.84 g, 10.4 mmol) in N,N-dimethylformamide (60 mL) was added copper(I) iodide (100 mg, 0.525 mmol). After the reaction was refluxed for 48 hours, it was allowed to cool to room temperature, and the solvent was removed in vacuo. The residue was partitioned between water and dichloromethane. The dichloromethane was dried (MgSO4) and concentrated to give a dark residue that was used in the next step with no further purification. LC-MS (C23H35NOSi calc'd 369) m/z 370 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]2[C:27]3[C:15](=[CH:16][C:17]4[C:18]([CH3:29])([CH3:28])[C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=5[C:25]=4[CH:26]=3)[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:5]=[C:4](Br)[N:3]=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:31]1([C:2]2[CH:7]=[C:6]([N:8]3[C:27]4[C:15](=[CH:16][C:17]5[C:18]([CH3:29])([CH3:28])[C:19]6[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=6[C:25]=5[CH:26]=4)[C:14]4[C:9]3=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:3]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)c1ccccc1n3-c1cc(Br)nc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(C)c2ccccc2-c2cc3c(cc21)c1ccccc1n3-c1cc(-c2ccccc2)nc(-c2ccccc2)c1

Procedure:
25 g (48 mmol) of 6-(2,6-dibromopyridin-4-yl)-12,12-dimethyl-6,12-dihydro-6-azaindeno[1,2-b]fluorene and 12.9 g of phenylboronic acid (106 mmol) are suspended in 300 ml of ethylene glycol dimethyl ether. 75 ml of a 2 M Na2CO3 solution are added to the reaction mixture. 2.8 g (2.4 mmol) of Pd(PPh3)4 are added to this suspension. The reaction mixture is heated under reflux for 12 h. After cooling, the solid which has precipitated out is filtered off with suction, washed with water and ethanol and dried. The residue is extracted with hot toluene, recrystallised from toluene and finally sublimed in a high vacuum, the purity is 99.9%. Yield: 18 g, 72% of theory.
Reaction SMILES: [OH-].[Na+].[CH:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]=[O:20])=[CH:14][CH:13]=1>O.CO>[F:11][C:12]1[CH:17]=[CH:16][C:15](/[C:18](=[CH:3]/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)/[CH:19]=[O:20])=[CH:14][CH:13]=1
Reactant: O=CCc1ccc(F)cc1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C/C(=C\c1ccccc1)c1ccc(F)cc1
Temperature: 10 °C
Reaction time: 10 h

Procedure:
4.2 g of sodium hydroxide in 30 ml of water are added to a solution of 26.5 g of benzaldehyde in 300 ml of methanol. The reaction mixture is cooled to 10° C., and 36 g of 4-fluorophenylacetaldehyde are rapidly added, during which the solution rises to 30°-40° C. The reaction solution is stirred at 40° C. for 10 hours and then cooled and the crystals which have separated out are filtered off with suction. 31.6 g (56%) of E/Z-2-(4-fluorophenyl)-3-phenylpropenal of melting point 87°-94° C. are obtained.