Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=S)=S.[CH2:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:9]=2[CH:10]=1)[CH3:5].[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[Sn](Cl)(Cl)(Cl)Cl>O>[C:17]([C:10]1[C:9]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:8]=2[O:7][C:6]=1[CH2:4][CH3:5])(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCc1cc2ccc(OC)cc2o1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: S=C=S
Solvent: O
Product: CCc1oc2cc(OC)ccc2c1C(=O)c1ccc(OC)cc1

Procedure:
Dried carbon disulfide solution (20 ml) of 2-ethyl-6-methoxy-benzofuran (2.76 g, 15.6 mmol) and p-anisoyl chloride (3.48 g, 20.3 mmol) was cooled on ice, to which tin chloride (IV) was dropped (5.25 g, 20.3 mmol) while stirring. The mixture was stirred at a temperature in a range of 5 to 10° C. for 3 hours and then poured into water. The organic layer was washed with diluted hydrochloric acid and water, dried over MgSO4, and concentrated under reduced pressure. Crude product thereof was purified by HPLC (silica gel, ethyl acetate: hexane=2:8) and a target product in pale yellow oily state (2.98 g, 9.60 mmol, 58%) was obtained.
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[CH2:11]([C:13]1[S:17][C:16]2[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:15]=2[CH:14]=1)[CH3:12]>>[CH2:11]([C:13]1[S:17][C:16]2[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:15]=2[C:14]=1[S:6]([Cl:10])(=[O:8])=[O:7])[CH3:12]
Reactant: CCc1cc2cc(C)ccc2s1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1sc2ccc(C)cc2c1S(=O)(=O)Cl

Procedure:
2-ethyl-5-methylbenzo[b]thiophene-3-sulfonylchloride was prepared in the same manner as described in Example 40B. Reaction of DMF (6.5 mmoles, 0.50 ml), sulfurylchloride (5.5 mmoles, 0.44 ml) and 2-ethyl-5-methylbenzo[b]thiophene (3.2 mmoles, 0.57 g) yielded, after flash chromatography, using 2% ethyl acetate/hexanes, 0.58 g (66%) of an orange solid.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:22][C:23]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:24]=1[NH2:25].C(Cl)Cl.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[CH:18]([O:17][CH:10]([CH3:9])[CH3:11])([CH3:19])[CH3:22].[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][C:24]1[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:23]=1[CH3:22])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Reactant: Cc1ccc(N)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(C)OC(C)C
Product: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccc(C)cc1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 150.8 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-(2-methylthioethoxy)quinoline (0.8 g, 2.5 mmol) and 2,4-dimethylaniline (0.45 g, 3.7 mmol) in toluene (12 ml) was heated to 90° C. and stirred 3.0 h. After cooling to room temperature, methylene chloride and water were added. The mixture was neutralized with a saturated solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and evaporated. Trituration with isopropyl ether gave 0.77 g (75%) of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH:14]=O)[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:14][NH:20][CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[Cl:16])[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCCC1(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCCC1(C)CNCc1ccccc1Cl
Reaction time: 0.33 h
Yield: 40 %

Procedure:
To a solution of (rac)-2-formyl-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.7 g, 1 eq) and 2-chloro-benzylamine (1.2 eq) in DCE (20 mL) was added acetic acid (0.8 eq) and allowed to stir for 20 minutes followed by the addition of sodium triacetoxyborohydride (2 eq). The reaction mixture was stirred for 12 h. After completion of reaction on TLC, the reaction was quenched with water and extracted with DCM (3×50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated using rotary evaporator to give sticky crude product, which was then purified with column chromatography (2-5% Methanol:DCM, Mesh Size-100-200 silica, Diameter of column—3.0 cm, Height of silica—approx. 4 inch) to afford the desired (rac)-2-[(2-chloro-benzylamino)-methyl]-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a sticky solid (40-70%).
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)([CH3:8])[CH3:7].CN1CCN(C)C1=O.O.C(O[CH:28](OCC)[N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[N:34][N+:35]([O-:37])=[O:36])C>>[CH:6]([C:9]1[CH:15]=[CH:14][C:12]([N:13]=[CH:28][N:29]2[CH2:33][CH2:32][NH:31][C:30]2=[N:34][N+:35]([O-:37])=[O:36])=[CH:11][CH:10]=1)([CH3:8])[CH3:7]
Reactant: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Reactant: CC(C)c1ccc(N)cc1
Agent: O=S(=O)(O)O
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: CC(C)c1ccc(N=CN2CCNC2=N[N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 41.6 %

Procedure:
0.05 g of concentrated sulfuric acid was dropped in a mixture of 5.0 g of 1-diethoxymethyl-2-nitroiminoimidazolidine, 2.48 g of p-isopropylaniline and 2 ml of 1,3-dimethyl-2-imidazolidinone at 110° C., followed by agitation at the same temperature for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried and evaporated. Ether was added to the resultant oily residue and the resultant crystals were separated by filtration and dried to obtain 2.1 g of 1-(4-isopropylphenyliminomethyl)-2-nitroiminoimidazolidine.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:20])=O.C(Cl)(Cl)Cl>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:20])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(C(=O)Cl)cc1[N+](=O)[O-]

Procedure:
4-Acetamido-3-nitrobenzoic acid 1 (Alfa Aesar, 5.6 g, 25 mmol), oxalyl chloride (4.76 g, 38 mmol), chloroform (50 ml), DMF (few drops) were stirred at 40° C. for 3 hours. The solvent was removed in vacuo to give a yellow solid that was used in the next step without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[OH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.CCOC(C)=O>CN(C=O)C>[C:21]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([O:17][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at room temperature, solid K2CO3 (30 mmol) was added followed by addition of 4-hydroxybiphenyl (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to room temperature to room temperature, the reaction mixture was poured into EtOAc (100 mL), washed with water (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuo to afford the desired 4-(biphenyl-4-oxy)-1-nitrobenzene. The crude product was used for further transformation .
Reaction SMILES: C([NH:4][C:5]1[C:23]([Cl:24])=[CH:22][C:8]([C:9]([NH:11][C@@H:12]2[CH2:16][N:15](C(=O)C)[C@H:14]([CH2:20][OH:21])[CH2:13]2)=[O:10])=[C:7]([O:25][CH3:26])[CH:6]=1)(=O)C.[OH-].[Na+].O>C(O)C>[ClH:24].[NH2:4][C:5]1[C:23]([Cl:24])=[CH:22][C:8]([C:9]([NH:11][C@@H:12]2[CH2:16][NH:15][C@H:14]([CH2:20][OH:21])[CH2:13]2)=[O:10])=[C:7]([O:25][CH3:26])[CH:6]=1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)N[C@H]1C[C@@H](CO)N(C(C)=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@@H]1CN[C@H](CO)C1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 107 %

Procedure:
11.74 g of 4-acetylamino-5-chloro-2-methoxy-N-[(2S,4S)-1-acetyl-2-hydroxymethyl-4-pyrrolidinyl]benzamide was dissolved in ethyl alcohol (60 ml), and sodium hydroxide (2.7 g) was added thereto. The mixture was heated at reflux for 8.5 hours. After addition of water (20 ml), the mixture was stirred at room temperature for 1 hour to filter insolubles off, and washed sufficiently with water (50 ml). The filtrate was concentrated under reduced pressure, n-butyl alcohol (50 ml) and a saturated brine solution (20 ml) were added to the resulting residue, and the layers were separated, followed by re-extraction with n-butyl alcohol (30 ml). The extract was concentrated under reduced pressure, methyl alcohol (50 ml) was added to the residue to dissolve it, and 18% (w/w) hydrochloric acid-containing methyl alcohol (6.5 g) was gradually added to adjust to a pH 6. After ice-cooling, precipitated crystals were filtered, and washed with a small amount of methyl alcohol. The resulting crystals were recrystallized from ethyl alcohol to obtain 5.5 g of the objective 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamide monohydrochloride. mp 219-222° C., [α]D20: +4.20 (c=1.00, EtOH)
Reaction SMILES: [Na:1].C(C1(C[CH2:15][O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][S:24]([C:26]3[NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[N:27]=3)=[O:25])[C:18]=2[CH3:35])OCC2(OCCO2)CO1)C.ClC1C=CC=C(C(OO)=O)C=1.[O:47]1[C:51]2([CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[O:50][CH2:49][CH:48]1CO>>[Na:1].[O:47]1[C:51]2([CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[O:50][CH2:49][C@@H:48]1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][S:24]([C:26]2[NH:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[N:30]=2)=[O:25])[C:18]=1[CH3:35]
Reactant: CCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCC2(CO1)OCCO2
Reactant: OCC1COC2(CCCCC2)O1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na]
Product: Cc1c(OC[C@H]2COC3(CCCCC3)O2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 16.8 %

Procedure:
The same procedure as in the steps (4f) to (4j) of Example 4 (a reprecipitation operation was not performed in oxidation step with 3-chloroperbenzoic acid) was repeated using (+)-1,4-dioxaspiro[4.5]decane-2-methanol to obtain the title compound (500 mg, total 16.8% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][C:30]1[CH:31]=[C:32]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:34]2[CH:33]=[C:32]([NH:45][S:46]([CH3:49])(=[O:47])=[O:48])[CH:31]=[C:30]([CH3:29])[CH:35]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1cc(NS(C)(=O)=O)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(NS(C)(=O)=O)cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 55.1 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (60 mg, 0.14 mmol) were added N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methane sulfonamide (141 mg, 45% purity, 0.20 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (11 mg, 0.01 mmol) and 136 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified by flash chromatography (50 to 100%, hexane-ethyl acetate) phase using SP1® Purification System to give 42 mg (55% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[O:15][C:16]3[C:22]([C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]>CO.C1COCC1.[Ni]>[NH2:28][CH2:27][C:26]1[CH:29]=[CH:30][C:23]([C:22]2[C:16]3[O:15][C:14]([NH:13][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=4)=[N:18][C:17]=3[CH:19]=[CH:20][CH:21]=2)=[CH:24][CH:25]=1
Reactant: COc1cc(Nc2nc3cccc(-c4ccc(C#N)cc4)c3o2)cc(OC)c1OC
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3cccc(-c4ccc(CN)cc4)c3o2)cc(OC)c1OC
Reaction time: 20 h

Procedure:
To a solution of 0.117 g (0.291 mmol) 4-[2-(3,4,5-trimethoxy-phenylamino)-benzooxazol-7-yl]-benzonitrile (example 19) in 5 ml MeOH (MeOH contains 5% NH3), 5 ml THF and 30 mg Ra—Ni (B113W EtOH, Degussa) are added. Then this mixture is hydrogenated under normal pressure for 20 h at room temperature. The reaction mixture is filtered (2 glass fiber filters used) and the filtrate is concentrated in vacuo. The residue is purified by crystallization from dichloromethane/diethyl ether to afford the title compound as a light grey solid. Rt=1.85 min (Waters Symmetry C8, 2.1×50 mm, detection 210-250 nM, 5% to 100% CH3CN in H2O in 2 min+0.05% TFA, flow rate 1.0 ml/min); MS: 406 (M+1)+; m.p. 208-211° C.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([CH2:21][CH2:22][CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CO>C(OCC)(=O)C>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:27]3[CH2:28][CH2:29][CH:24]([CH2:23][CH2:22][CH2:21][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:25][CH2:26]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(CCCc2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(3-phenylpropyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 73% overall yield. FDMS m/e=392 (M+ of free base). α[D]589 =-13.53 (c=0.58, methanol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([N:10]2[C:15](=[O:16])[CH2:14][CH:13]([C:17]([F:20])([F:19])[F:18])[CH2:12][C:11]2=[O:21])=[C:4]([F:22])[CH:3]=1.[CH2:23]([OH:26])[CH2:24]O.O.[C:28]1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH:8]2[O:26][CH2:23][CH2:24][CH2:28][O:9]2)=[CH:6][C:5]([N:10]2[C:11](=[O:21])[CH2:12][CH:13]([C:17]([F:19])([F:18])[F:20])[CH2:14][C:15]2=[O:16])=[C:4]([F:22])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCO
Reactant: O=Cc1cc(N2C(=O)CC(C(F)(F)F)CC2=O)c(F)cc1Cl
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CC(C(F)(F)F)CC(=O)N1c1cc(C2OCCCO2)c(Cl)cc1F
Yield: 2527 %

Procedure:
To 3.4 g (.10 mmol) N-(4'-chloro-2'-fluoro-5'-formylphenyl)-3-(trifluoromethyl)glutarimide (Compound 94) in 110 ml toluene was added 0.94 g (15 mmol) ethylene glycol and a catalytic amount of p-toluenesulfonic acid monohydrate (0.48 g, 2 mmol). The mixture was refluxed for 72 h with removal of water via a Dean-Stark trap. The solvent was removed in vacuo and the residue was partitioned between EtOAc and water. The organics were washed with water and brine, dried over MgSO4, then filtered and concentrated to leave 4.1 g (105 % yield) of an oily taffy containing mostly product by NMR analysis. Recrystallization from Et2O afforded 1.0 g of the 1,3-dioxane as a pale yellow solid, m.p. 158°-161° C.
Reaction SMILES: C([S:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[N:22]([CH3:23])[C:21]3[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:20]=3[N:19]=2)=[CH:12][CH:11]=1)[C:6]([OH:8])=O)(=O)C.C([N:32](CC)CC)C.ClCCOC=O.N>CN(C)C=O.O1CCCC1>[SH:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[N:22]([CH3:23])[C:21]3[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:20]=3[N:19]=2)=[CH:12][CH:11]=1)[C:6]([NH2:32])=[O:8]
Reactant: CCN(CC)CC
Reactant: COc1ccc2nc(COc3ccc(CC(SC(C)=O)C(=O)O)cc3)n(C)c2c1
Agent: N
Agent: O=COCCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2nc(COc3ccc(CC(S)C(N)=O)cc3)n(C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.3 %

Procedure:
A mixture of 2-acetylthio-3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]propionic acid (1.53 g), anhydrous triethylamine (0.4 g), chloroethylformate (0.65 g), anhydrous tetrahydrofuran (10 ml) and anhydrous N,N-dimethylformamide (10 ml) was stirred at room temperature for 1 hour. An aqueous solution of ammonia (20 ml, 28%) was added to the reaction mixture and this mixture was stirred for 2 hours and then allowed to stand overnight. The reaction mixture was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by liquid chromatography (LiChroprepNH2 (Merck)) using ethanol:ethyl acetate=1:12 as the eluant to afford the title compound (0.21 g, mp 204-208° C.) as a pale yellow powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11](=[O:17])[CH:10]=[CH:9]2.[CH3:18][N:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30])[C:20](=[O:23])[CH:21]=[CH2:22]>C(O)C>[CH3:18][N:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30])[C:20](=[O:23])[CH2:21][CH2:22][NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11](=[O:17])[CH:10]=[CH:9]2
Reactant: Cn1c(=O)ccc2cc(OCCCN)ccc21
Reactant: C=CC(=O)N(C)c1ccccc1C
Solvent: CCO
Product: Cc1ccccc1N(C)C(=O)CCNCCCOc1ccc2c(ccc(=O)n2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
6-(3-Amino-propoxy)-1-methyl-1H-quinolin-2-one(194 mg) was added to an ethanol solution (5 ml) of N-methyl-N-o-tolyl-acrylamide(146 mg). The mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol=20:1→10:1). The purified product was condensed under reduced pressure to give the title compound(172.6 mg) as a colorless oil.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][NH:10]C(=O)OC(C)(C)C)[CH2:5][CH2:4]1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH2:10][CH2:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([C:1]#[N:2])[CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C#N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#C[C@H]1CC[C@H](CN)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (trans-4-cyanocyclohexyl)methylcarbamate (500 mg) in dichloromethane (10 mL) was slowly added trifluoroacetic acid (2 mL) at 0° C. The reaction mixture was warmed to room temperature, stirred for 1 hour and concentrated to provide the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH2:9]O)[CH:2]=1.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:12][CH2:9][CH2:8][O:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCOc1cccnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCOc1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
A solution of 2-(pyridin-3-yloxy)-ethanol (200 mg) in 5 mL dichloromethane was cooled to 0° C. and treated with carbon tetrabromide (524 mg) followed by triphenylphosphine (415 mg) portionwise. The reaction mixture was stirred at 0° C. for 30 mins then at room temperature for 45 mins. The volatiles were evaporated and the residue purified by silica gel chromatography eluting with 0-100% EtOAc/pentane to give the title compound (204 mg) as a colourless liquid which was used without further purification.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4](=O)[NH:3][CH:2]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:4]1[C:5]2[CH:9]=[CH:8][NH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=c1[nH]cnc2[nH]ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2[nH]ccc12
Yield: 70 %

Procedure:
3,7-Dihydro-pyrrolo[2,3-d]pyrimidin-4-one (60 mg, 0.45 mmol) was reacted with 3.0 mL of phosphorus oxychloride to give 49 mg (70%) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.57 (s, br, 1H, NH), 8.58 (s, 1H), 7.68 (dd, J=2.53, 3.36 Hz, 1H), and 6.59 (dd, J=1.86, 3.36 Hz, 1H). MS m/e 153 [M-1]+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[P:14]([OH:17])([OH:16])[OH:15].P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:9][CH2:10][C:11]([P:14]([OH:17])([OH:16])=[O:15])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:2]
Reactant: CCCCCN(C)CCC(=O)O
Reactant: OP(O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClP(Cl)Cl
Product: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 57.5 °C
Reaction time: 10 h

Procedure:
3-(N-Methyl-N-pentylamino)propanoic acid hydrochloride (100 g) was suspended in toluene (300 mL) and polyethylene glycol 400 (120 mL). Phosphorous acid (43.01 g 1.1 eq.) was added to the mixture. The mixture was warmed and phosphorous trichloride (98.22 g, 1.5 eq.) was added at a rate such that the temperature remained below 60° C. The mixture was stirred for 10 hours at 55-60° C. whereupon it was quenched by adding water (450 mL). The water addition was controlled to maintain a reaction temperature below 70° C. The layers were separated and the aqueous layer was refluxed for 6 hours. The mixture was cooled to 40-45° C. to provide Ibandronic acid in solution and the pH was adjusted to 4.3-4.5 using 50% aqueous sodium hydroxide. Propylene glycol (150 mL) was then added to the reaction mixture at 60-65° C. and stirred for 4-5 hours. The mixture was cooled to 20-25° C. over a period of 2-3 hours and then for 3-4 hours at 0-5° C., filtered, washed with acetone (2×150 mL) and dried in vacuo.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH:16]1([N:13]2[CH2:12][CH2:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1ccc(C2CCN(C3CCCC3)CC2)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
4-(4-Nitrophenyl)piperidine (5 g, 24 mmol) was dissolved in MeOH (240 mL). To the solution were added cyclopentanone (6.5 mL, 73 mmol) and acetic acid (3 mL). The mixture was stirred for 1 hour, and then NaBH3CN (6.1 g, 97 mmol) was added. The mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, and the residue was suspended in EtOAc. The organic suspension was washed with 1N NaOH (aq), water and brine, dried, concentrated and purified by flash column chromatography (MeOH/DCM) to obtain 1-cyclopentyl-4-(4-nitrophenyl)piperidine (303) (6.5 g, 24 mmol, 100% yield).