Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][NH:11][C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[I-].[K+].[CH3:40][C:41]([CH2:43]C(C)C)=O>>[CH2:43]([N:11]1[CH2:12][C@@H:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:41]=[CH2:40]
Reactant: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Reactant: CC(=O)CC(C)C
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: C=CCN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
(2R,3R,4R)-3,4-Dibenzyloxy-2-benzyloxymethylpyrrolidine (Compound 1) (1.025 g, 2.5 mmol) was dissolved in methylisobutylketone (15 ml). Triethylamine (0.53 ml, 3.8 mmol) and potassium iodide (0.04 g) were added. The mixture was stirred under a nitrogen atmosphere for 4 hours at 80° C. and 24 hours at room temperature and evaporated in vacuo. Water (40 ml) was added and extraction with methylene chloride (3×40 ml), drying of the organic phases with magnesium sulphate and evaporation of the solvent in vacuo afforded a yellow oil. Purification of the crude product on a silica gel column (Eluent: Heptane/ethyl acetate (9: 1)) gave (2R,3R,4R)-1-allyl-3,4-dibenzyloxy-2-benzyloxymethylpyrrolidine (0.91g, yield: 81%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Cl[C:12]([S:14]Cl)=[O:13]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][C:12](=[O:13])[S:14][N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)SCl
Reactant: NC(=O)c1ccc(F)cc1
Solvent: Cc1ccccc1
Product: O=c1oc(-c2ccc(F)cc2)ns1
Temperature: 60 °C

Procedure:
To a stirred suspension of 4-fluorobenzamide (70.00 g, 503.1 mmol) in toluene (900 mL) was added chlorocarbonyl sulfenyl chloride (83.0 mL, 1.00 mol). The mixture was heated overnight at 60° C. and concentrated. The resulting tan solid was triturated with methylene chloride (200 mL), collected by suction filtration and rinsed with additional methylene chloride (4×70 mL). The crude product was impregnated onto silica (100 g) and chromatographed in a large filter funnel dry loaded with silica using a hexane/ethyl acetate gradient. The product 5(4-fluorophenyl)-1,3,4-oxathiazol-2-one was afforded as an off-white solid (55.98 g, 56%).
Reaction SMILES: [CH:1]1([N:4]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=3[F:20])[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:27][C:28]1([CH3:31])[O:30][CH2:29]1>>[CH:1]1([N:4]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]([OH:30])([CH3:31])[CH3:29])[CH2:23][CH2:22]2)[C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=3[F:20])[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(-c2cc(C(=O)N(C3CCNCC3)C3CC3)on2)c(F)c1
Reactant: CC1(C)CO1
Product: CC(C)(O)CN1CCC(N(C(=O)c2cc(-c3ccc(C#N)cc3F)no2)C2CC2)CC1

Procedure:
The title compound is prepared from 3-(4-cyano-2-fluoro-phenyl)-isoxazole-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide and 1,1-dimethyloxirane following a procedure analogous to that described for Intermediate 2. LC (method 4): tR=1.19 min; Mass spectrum (ESI+): m/z=427 [M+H]+.
Reaction SMILES: [CH2:1]([C@H:8]1[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)OC(=O)[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.CC(O)=O.[Pd]>[NH2:9][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:12]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: O=C1N[C@@H](Cc2ccccc2)C(c2ccccc2)(c2ccccc2)O1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: N[C@@H](Cc1ccccc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
A solution of (S)-4-benzyl-5,5-diphenyl-2-oxazolidinone (7) (940 mg, 2.85 mmol) in MeOH/AcOH and a 10% Pd (121 mg, 1.14 mmol) on activated carbon was shaken for 43 h under 4–5 atm pressure of hydrogen at room temperature. The catalyst was filtered off over Hyflo Super Cell and organic solvents were evaporated under reduced pressure. The resulting residue was treated with HCl, stirred for 2 h at room temperature, made basic with NaOH pellets, and saturated with K2CO3 and NaCl. Organics were then extracted into dichloromethane (4×50 ml), dried over MgSO4/K2CO3 and concentrated under reduced pressure to obtain a crude product. Purification over silica gel, eluting with a 3:7 and 4:6 mixture of AcOEt and petroleum ether, gave the title compound (8) (584 mg, 71%) as a light-brown solid. m.p. 71–72° C. [α]D25=−8.03° (c, 0.1046 in CHCl3). δH 1.21 (2H, broad s, NH2), 2.29 (1H, dd, 3J=9.6 Hz, 2J=13.5 Hz, CH2—Ph), 2.79 (1H, dd, 3J=2.1 Hz, 2J=13.2 Hz, CH2—Ph), 3.71 (1H, d, 3J=9.9 Hz, CH—Ph2), 3.81 (1H, ddd, 3J=2.7, 9.9 and 12.6 Hz, CH—NH2), 7.06–7.33 (15H, m, Ar—H), δC 41.9 (CH2—Ph), 55.7 and 59.7 (CH—Ph2 and CH—NH2), 126.3, 126.5, 126.6, 128.1, 128.2, 128.4, 128.7, 128.8 and 129.1 (o-, m- and p-Ar), 139.7, 142.6 and 143.1 (α-Ar). ir 3387 (NH2). m/e (CI—NH3) 288 (MH+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1)[CH2:19][CH2:20][C:21](=[O:23])[NH2:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:30][C:31]([F:41])([F:40])[CH2:32][S:33]([CH2:36][C:37](O)=[O:38])(=[O:35])=[O:34].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH:16][C:37](=[O:38])[CH2:36][S:33]([CH2:32][C:31]([F:40])([F:30])[F:41])(=[O:34])=[O:35])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1)[CH2:19][CH2:20][C:21](=[O:23])[NH2:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CS(=O)(=O)CC(F)(F)F
Reactant: CC(C)(C)OC(=O)C1=C(C(CCC(N)=O)Sc2nnn[nH]2)CS[C@@H]2C(N)C(=O)N12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1=C(C(CCC(N)=O)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)CS(=O)(=O)CC(F)(F)F)C(=O)N12
Reaction time: 12 h

Procedure:
To a solution of 8.4 g. (0.019 mol.) of 7-amino3-[1-(2-carbamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem4-carboxylic acid t-butyl ester and 3.9 g. (0.019 mol.) of 2,2,2-trifluoroethylsulfonylacetic acid in tetrahydrofuran is added dropwise a solution of 3.9 g. (0.019 mol.) of dicyclohexylcarbodiimide in 100 ml. of tetrahydrofuran. The reaction mixture is stirred at 25° for 12 hours, then filtered and concentrated to about 10 ml. The residue is filtered and evaporated to dryness to give 7-(2,2,2-trifluoroethylsulfonylacetamido)-3-[1-(2-carbamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21]>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)C(C)(C)N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)C(C)(C)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-aminoisobutyrate (prepared from 2-aminoisobutyric acid (Aldrich) using General Procedure H), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.25 in CHCl3/MeOH 95:5).
Reaction SMILES: OS(O)(=O)=O.[O:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][CH2:7]1.[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][CH:21]=1>C(O)(=O)C>[O:16]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:6][CH2:7][C:8]1=[CH:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([O:18][CH3:17])=[O:28])=[CH:21][CH:22]=1
Reactant: O=C1CCOc2ccccc21
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C=C2COc3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.2 %

Procedure:
Concentrated H2SO4 (2 ml) was slowly added to a solution of 4-chromanone (2.00 g, 13.50 mmol) and methyl-4-formylbenzoate (2.11 g, 12.86 mmol) in glacial acetic acid. The reaction mixture was stirred 16 h at room temperature. The solvent was concentrated to half volume the resulting precipitate was filtered and rinsed with ethyl acetate to afford the title compound 260 (3.11 g, 82%) as a purple solid. 1H NMR: (DMSO) δ (ppm): 8.05 (d, J=8.2 Hz, 2H), 7.90 (d, J=7.6 Hz, 1H), 7.79 (s, 1H), 7.64-7.59(m, 3H), 7.15 (dd, J=7.6, 7.6 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 5.43 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[O:4][CH2:3]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:45][CH2:46][C:47]1[C:48]([OH:55])=[N:49][C:50]([CH3:54])=[CH:51][C:52]=1[CH3:53]>ClCCl>[OH:55][C:48]1[C:47]([CH2:46][NH:45][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[CH:2]([CH3:1])[CH2:3][O:4][C:5]=3[CH:10]=2)=[O:13])=[C:52]([CH3:53])[CH:51]=[C:50]([CH3:54])[N:49]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC1COc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc3c(c2)OCC3C)c(O)n1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of 3-methyl-2,3-dihydrobenzofuran-6-carboxylic acid (100 mg, 0.56 mmol) in dichloromethane (50 mL) was added 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (35 mg, 0.5 mmol), triethylamine (32 mg, 0.7 mmol), stirred for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (27 mg, 0.4 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was washed with water (50 mL), dried over sodium sulphate, concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give the product N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-3-methyl-2,3-dihydrobenzofuran-6-carboxamide (75 mg, 43%) as white solid. LRMS (M+H+) m/z: calcd 367.23. found 367. HPLC Purity (214 nm): 97%. 1H NMR (300 MHz, CDCl3) δ 7.32-7.27 (m, 2H), 7.12-7.11 (m, 1H), 6.10 (s, 1H), 4.72-4.66 (m, 1H), 4.46 (s, 2H), 4.11-4.05 (m, 1H), 3.56-3.53 (m, 1H), 2.35 (s, 3H), 2.24 (s, 3H), 1.31 (d, J=7.2 Hz, 3H).
Reaction SMILES: [Si]([O:18][C:19]1[CH:64]=[CH:63][C:22]([O:23][CH2:24][C@@H:25]([OH:62])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:61]=[CH:60][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([CH:43]4[CH2:48][CH2:47][N:46]([C:49]([NH:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[O:50])[CH2:45][CH2:44]4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:52]([NH:51][C:49]([N:46]1[CH2:47][CH2:48][CH:43]([C:41]([N:38]2[CH2:37][CH2:36][CH:35]([NH:34][C:33]3[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:62])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:64][CH:63]=4)=[CH:61][CH:60]=3)[CH2:40][CH2:39]2)=[O:42])[CH2:44][CH2:45]1)=[O:50])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]
Reactant: CCCCCCCCNC(=O)N1CCC(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)CC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)N1CCC(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)CC1
Yield: 16.7 %

Procedure:
4-({4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinyl}carbonyl)-N-octyl-1-piperidinecarboxamide (0.160 g, 0.180 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.02 g, 0.03 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][N:23](C)[CH3:24])([C:8](=O)C2C=CC=CC=2)N[CH:7]=1.[N:26]#[C:27]Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:22][N:23]=[C:24]([C:4]3[CH:3]=[CH:2][CH:7]=[CH:27][N:26]=3)[C:8]=2[CH:7]=1
Reactant: CN(C)Cc1ccccc1C1(C(=O)c2ccccc2)C=CC(Cl)=CN1
Reactant: N#CBr
Solvent: ClCCl
Product: Clc1ccc2c(c1)C(c1ccccn1)=NCc1ccccc1-2

Procedure:
The solution of 4.5 g of 5-chloro-2-(o-dimethylaminomethyl-phenyl)-2-benzoylpyridine in 120 ml of methylene chloride is treated during 4 hours with 13.7 ml of 0.94 molar cyanogen bromide in methylene chloride. The mixture is evaporated, the residue dissolved in 200 ml of saturated methanolic ammonia, and the solution evaporated after 2 days. The residue is taken up in aqueous sodium carbonate, the mixture extracted with diethyl ether, the extract washed with saturated aqueous sodium chloride, decolorized with activated charcoal, evaporated and the residue crystallized from diethyl ether to give the 9-chloro-7-(2-pyridyl)-5H-dibenz[c,e]azepine melting at 153°-155°.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:12]1([O:11][C:4]2[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=[C:2]([O:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ncc(Cl)cc1OC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ncc(Oc2ccccc2)cc1OC1CCCC1
Temperature: 100 °C
Yield: 60 %

Procedure:
5-Chloro-3-cyclopentyloxy-2-nitro-pyridine (0.8 mmol) is dissolved in DMF (8 ml), phenol (3 eq.) and K2CO3 (4 eq.) is added. The reaction mixture is heated to 100° C. in the microwave for 60 min. The reaction solution is pored into water and extracted with methyl-tert.-butyl ether. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 3-Cyclopentyloxy-2-nitro-5-phenoxy-pyridine is obtained after column chromatography (heptane/ethyl acetate) as yellow oil in a yield of 60%; HPLC (method C): 2.23 min; LC-MS (method A): 2.31 min, 301.15 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:41]=[CH:40][C:29]([O:30][CH2:31][C:32]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[O:33])=[CH:28][CH:27]=1>O1CCOCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([O:30][CH2:31][C:32]([N:34]2[CH2:39][CH2:38][N:37]([C:2]3[C:3]4[CH:10]=[C:9]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=5)[S:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH2:36][CH2:35]2)=[O:33])=[CH:40][CH:41]=1
Reactant: Fc1ccc(-c2cc3c(Cl)ncnc3s2)cc1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(COc1ccc(Cl)cc1)N1CCN(c2ncnc3sc(-c4ccc(F)cc4)cc23)CC1
Temperature: 60 °C
Yield: 69.9 %

Procedure:
To a solution of 4-chloro-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine (20 mg, 0.08 mmol) and triethylamine (42 μl, 0.3 mmol) in dioxane (1 ml) was added 2-(4-chlorophenoxy)-1-(piperazin-1-yl)ethanone (25 mg, 0.1 mmol). The mixture was heated at 60° C. for 2 hours. After cooling down to room temperature, the solvents were removed under reduced pressure. The crude residue was purified by silica gel chromatography (CH2Cl2/MeOH 50:1) to yield the title compound as a white solid (27 mg, 75%).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14].CS(O)(=O)=O.[CH3:20][OH:21]>>[CH3:20][O:21][C:6]1[C:5]2[C:10](=[CH:11][CH:2]=[C:3]([O:13][CH3:14])[CH:4]=2)[C:9](=[O:12])[NH:8][CH:7]=1
Reactant: CO
Reactant: COc1cc2cc[nH]c(=O)c2cc1F
Agent: CS(=O)(=O)O
Product: COc1ccc2c(=O)[nH]cc(OC)c2c1
Yield: 48.8 %

Procedure:
To a solution of 7-fluoro-6-methoxyisoquinolin-1(2H)-one (7 g, 40.0 mmol) in methanol (70 ml) was added iodozobenzenediacetate (14.16 g, 40.0 mmol) followed by methane sulphonic acid (11.52 g, 120 mmol) at room temperature. The reaction mass was heated at reflux for 3 h. The solvent was evaporated and the residue was diluted with cold water. The precipitated solid was filtered, washed with water to get crude compound (4 g, 48.8%) as a light red colored solid. 1H NMR (400 MHz, DMSO): δ ppm 8.11-8.09 (d, J=8 Hz, 1H), 7.19 (s, 1H), 7.13-7.11 (d, J=8 Hz, 1H), 6.72-6.71 (d, J=12 Hz, 1H), 3.89 (s, 3H), 3.79 (s, 3H); MS: MS m/z 206.1 (M++1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][N:3]=1.[OH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.CC(C)([O-])C.[K+]>O1CCCC1.O>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][N:3]=1
Reactant: OCc1ccccn1
Reactant: CCOC(=O)c1cnc(Cl)nc1NCc1ccc(OC)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cnc(OCc2ccccn2)nc1NCc1ccc(OC)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (prepared in Example 95) 356 mg and 2-hydroxymethylpyridine 109 mg in anhydrous tetrahydrofuran 4.5 ml is added potassium tert-butoxide 112 mg under ice cooling, and the mixture is stirred for 30 minutes. The reaction mixture is diluted with water, extracted twice with ethyl acetate. The combined organic layer is washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel chromatography (silica gel 10 g, solvent; chloroform:ethyl acetate=5:1→2:1) and concentrated in vacuo to give 2-(2-pyridylmethoxy)-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (the compound prepared in Example 67-(3)) as a colorless caramel, 338 mg, which is crystallized on standing at room temperature overnight. mp 90-92° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][N:21]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=[CH:7][CH:8]=1.O.NN>C(O)C>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][NH2:21])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.6 %

Procedure:
1.41 g (3.08 mmol) of 2-((3-((3-(trifluoromethyl)phenyl)ethynyl) imidazo[1,2-a]pyridin-2-yl)methyl) isoindoline-1,3-dione were solubilised in 30 ml of ethanol with magnetic stirring, 0.978 ml (30.8 mmol) of hydrazine monohydrate were added. The mixture gradually became milky and was stirred at r.t. for 1.5 h. The suspended solid was isolated by filtration and washed with 2×25 ml of ethanol. The filtrate was concentrated in vacuo. The residue was triturated in 20 ml of ethanol, the solid was isolated by filtration and the filtrate concentrated in vacuo in order to obtain 0.715 g (yield=69%) of (3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methanamine as a pale yellow solid. LC-MS: m/z=316 (MH+); UV purity at 254 nm=94%. 1H NMR (300 MHz, DMSO) δ 8.73 (d, J=6.7 Hz, 1H), 8.12 (s, 1H), 7.98 (d, J=7.7 Hz, 1H), 7.82-7.63 (m, 3H), 7.49-7.40 (m, 1H), 7.13 (td, J=6.8, 1.1 Hz, 1H), 3.96 (s, 2H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.[Cl-].[Na+].O>[CH2:17]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=1)[C:9]1[N:10]=[CH:11][CH:12]=[CH:13][N:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Ic1ccc(N(Cc2ccccc2)c2ncccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, N-(4-iodophenyl)pyrimidin-2-amine (75 mg) was added to a suspension of sodium hydride (16 mg) in anhydrous DMF (3 ml), and the resulting mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled to 0° C. and benzyl bromide (0.039 ml) was added thereto, followed by stirring the resulting mixture at room temperature for 1 hour. Saturated brine was added to the reaction solution and the resulting mixture was extracted 3 times with ethyl acetate. Organic layers were washed 3 times with water and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:ethyl acetate/hexane=1/15) to obtain N-benzyl-N-(4-iodophenyl)pyrimidin-2-amine (67 mg).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH:12]([CH3:19])[N:13](CC)[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:20])[CH:4]=1.C(O[CH:26](O)[C:27]([F:30])([F:29])[F:28])C>>[F:22][C:2]([F:1])([F:21])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH:12]([CH3:19])[N:13]([CH2:26][C:27]([F:28])([F:29])[F:30])[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:20])[CH:4]=1
Reactant: CCOC(O)C(F)(F)F
Reactant: CCN1c2cc3c(C(F)(F)F)cc(=O)[nH]c3cc2CCC1C
Product: CC1CCc2cc3[nH]c(=O)cc(C(F)(F)F)c3cc2N1CC(F)(F)F

Procedure:
This compound was prepared in a similar fashion as that described in Example 84 from Compound 187 (Structure 33 of Scheme VI, where R1=methyl, n=1) and trifluoroacetaldehyde ethyl hemiacetal. 1H NMR (400 MHz, CDCl3) 11.08 (br. s, 1H), 7.06 (s, 1H), 7.00 (s, 1H), 6.99 (s, 1H), 3.99 (m, 1H), 3.81 (m, 1H), 3.67 (m, 1H), 3.10–2.95 (m, 1H), 2.92–2.82 (m, 1H), 2.07–1.97 (m, 1H), 1.93–1.80 (m, 1H), 1.19 (d, 3H, J=6.5).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:26](Br)=[N:25][C:24]([Br:28])=[CH:23][N:22]=1)(=[O:19])=[O:18]>>[Br:28][C:24]1[N:25]=[C:26]([O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:21]([NH:20][S:17]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=2[Cl:9])(=[O:19])=[O:18])=[N:22][CH:23]=1
Reactant: OCc1cccnc1
Reactant: O=S(=O)(Nc1ncc(Br)nc1Br)c1cccc(Cl)c1Cl
Product: O=S(=O)(Nc1ncc(Br)nc1OCc1cccnc1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using pyridine-3-methanol (0.44 g) and 2,3-dichloro-N-(3,5-dibromo-2-pyrazinyl)benzenesulphonamide (1.0 g). Yield 0.6 g.
Reaction SMILES: [Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][C@@H:10]2[CH2:12][C@H:7]1[CH2:8][N:9]2C(OC(C)(C)C)=O)=[O:5].CO.Cl>O1CCOCC1>[Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][C@@H:10]2[CH2:12][C@H:7]1[CH2:8][NH:9]2)=[O:5]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1cccc(Cl)c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1cccc(Cl)c1Cl)N1C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 5.5 g of tert-butyl (1S,4S)-5-(2,3-dichlorobenzoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and 10 ml of methanol was added hydrochloride in 1,4-dioxane solution (4 mol/l, 20 ml) followed by stirring for 1.5 hour at room temperature. The reaction mixture was concentrated in vacuo and then the resulting residue was suspended with diethylether. The precipitate was filtered and dried to give a crystal of the title compound.