Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)NC1C=CC=C([CH2:14][N:15]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:40])[C@@H:22]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31](Cl)[CH:30]=3)[CH2:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:16]2)C=1)(C)(C)C.[C:42](Cl)(=[O:46])[C:43](Cl)=[O:44].N1C(C)=CC=C[C:49]=1C>C(Cl)Cl.CN(C)C=O>[CH:24]1([CH2:23][C@H:22]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:31]([CH3:49])[CH:30]=2)[C:21]([NH:20][C:17]2[CH:18]=[CH:19][N:15]([CH2:14][C@@H:42]([OH:46])[CH2:43][OH:44])[N:16]=2)=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Reactant: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc([C@@H](CC2CCCC2)C(=O)Nc2ccn(C[C@@H](O)CO)n2)ccc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 57, 360 mg, 1.16 mmol) was dissolved in methylene chloride (8 mL) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 640 μL, 1.27 mmol) and N,N-dimethylformamide (one drop) and it was then stirred at 0° C. for 20 minutes and 30 minutes at 25° C. After this time, the reaction was concentrated in vacuo. In a separate flask a solution of 3-(3-amino-pyrazol-1-yl)-propane-(R)-1,2-diol (prepared as in Example 35, 200 mg, 1.27 mmol), 2,6-lutidine (200 μL, 1.74 mmol) and methylene chloride (6 mL) was cooled to 0° C. in an ice bath. To this solution was added the solution of the prepared acid chloride diluted with another portion of methylene chloride (8 mL) dropwise. After addition was complete the reaction was stirred at 0° C. for 30 minutes then allowed to warm to 25° C. and stirred for 18 h. After this time the reaction was diluted with methylene chloride (20 mL) and washed with a saturated aqueous sodium bicarbonate solution (20 mL) and a 1 N aqueous hydrochloric acid solution (20 mL). Each aqueous phase was backextracted with ethyl acetate (30 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification an AnaLogix Intelliflash system (80 g column, 100% ethyl acetate) afforded (R)-3-cyclopentyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (220 mg, 42%) as an off-white solid: [α]30589=+5.80° (c=0.65, methanol); ES-HRMS m/e calcd for C22H31N3O5S (M+H)+ 450.2057, observed 450.2057; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.09 (m, 2H, CH2), 1.33-1.81 (m, 8H, 4×CH2), 2.10 (m, 1H, CH), 2.61 (s, 3H, ArCH3), 3.17 (s, 3 H, SO2CH3), 3.26 (s, 2H, OCH2), 3.72 (brm, 1H, OCH), 3.82 (dd, J=7.6 Hz, 13.5 Hz, 1H, NCH of NCH2), 3.83 (m, 1H, ArCHCO), 4.05 (dd, J=4.0 Hz, 13.5 Hz, 1H, NCH of NCH2), 4.70 (t, J=5.6 Hz, 1H, OH), 4.92 (d, J=5.3 Hz, 1H, OH), 6.41 (d, J=2.3 Hz, 1H, Ar), 7.44 (m, 2H, Ar), 7.50 (d, J=2.3 Hz, 1H, Ar), 7.84 (d, Jo=8.7 Hz, 1H, Ar), 10.74 (s, 1H, NH).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN([P+](ON1N=[N:32][C:27]2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CN1CC[O:45][CH2:44]C1>C(#N)C.CCOC(C)=O>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][CH2:10][C:11](=[O:13])[NH:32][CH2:27][O:45][CH3:44])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CN1CCOCC1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COCNC(=O)CCNC(=O)OC(C)(C)C

Procedure:
A solution of BOC-beta-alanine (20 g, 105 mmol), 10-2 (10.3 g, 105 mmol), BOP reagent (46.5 g, 105 mmol), and N-methylmorpholine (46 mL, 420 mmol) in acetonitrile (500 mL) was stirred for 15 h. The reaction was diluted with EtOAc, washed with H2O, 10% KHSO4(aq.), sat. NaHCO3, dried (MgSO4) and concentrated to give crude [2-(methoxymethyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester 10-3 as a yellow oil. TLC Rf=0.42 (silica, 20% EtOAc/hexanes). To a solution of this crude amide in THF (500 mL) at 0° C. was added CH3MgBr (100 mL of 3M in ether, 300 mmol) over 30 minutes. After 2 h, 10% KHSO4(aq.) was added, the mixture warmed to 25° C., and diluted with EtOAc. The organics were washed with sat. NaHCO3, dried (MgSO4) and concentrated. Flash chromatography (silica, 20% EtOAc/hexanes) gave 10-4 as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]=[CH:8][C:9]2=[O:14])([O-])=O.[N+]([C:19]1[CH:20]=C2C(=[CH:27][CH:28]=1)C(=O)C=CC2=O)([O-])=O.[OH-].[Na+].[H][H]>[Pd]>[NH2:1][C:4]1[C:5]2[C:6](=[O:15])[C:7]3[C:8](=[CH:20][CH:19]=[CH:28][CH:27]=3)[C:9](=[O:14])[C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Reactant: O=C1C=CC(=O)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Yield: 94.2 %

Procedure:
25.7 Grams (0.1 mol) of crude 5-nitrotetrahydroanthraquinone obtained by condensing in ethanol 1,3-butadiene and 5-nitro-1,4-naphthoquinone containing therein 10% of 6-nitro-1,4-naphthoquinone was placed in a reactor having an inner volume of 2 liters together with 514 grams (0.13 mol) of a 1% aqueous sodium hydroxide solution and 0.52 gram of a 5% palladium on carbon catalyst and was hydrogenated with hydrogen at room temperature and under normal pressure with agitation. The hydrogenation reaction was stopped when 0.2 mol of hydrogen was abosrbed. Into the resultant reaction solution was fed air for oxidizing the over-reduced compound formed. The resultant reaction product was separated by filtration together with the catalyst. The thus separated product was mixed with N,N-dimethylformamide for dissolving the product alone, followed by separation of the catalyst by filtration. The resultant filtrate was diluted with water for precipitation to obtain 21 grams of 1-aminoanthraquinone containing therein 2% of 2-aminoanthraquinone (at a yield of 94.2%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:20]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:19]([CH2:28][CH3:29])=[N:18][C:12]=3[C:13]([NH2:17])=[N:14][C:15]=2[CH:16]=1.C(N(CC)CC)C.[C:37](OC(=O)C)(=[O:39])[CH3:38]>ClCCl>[NH2:17][C:13]1[C:12]2[N:18]=[C:19]([CH2:28][CH3:29])[N:20]([CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:11]=2[C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][NH:3][C:37](=[O:39])[CH3:38])=[CH:16][C:15]=2[N:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCc1nc2c(N)nc3cc(OCCN)ccc3c2n1CC1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(N)nc3cc(OCCNC(C)=O)ccc3c2n1CC1CCOCC1
Reaction time: 0.17 h
Yield: 75.3 %

Procedure:
7-(2-Aminoethoxy)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride (0.480 g, 1.03 mmol; prepared as in Example 552), dichloromethane (10 mL), and triethylamine (0.430 mL, 3.09 mmol) were combined and stirred for 10 minutes. Acetic anhydride (0.097 mL, 1.03 mmol) was added and the reaction was stirred for an additional 16 hours. The reaction mixture was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-20% CMA in chloroform). Fractions containing product were combined and concentrated. Trituration of the product in acetonitrile provided 0.319 g of N-(2-{[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)acetamide as fine white crystals, mp 165-167° C.
Reaction SMILES: [CH:1]([N:4]([CH3:22])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[C@H:7]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:6]1)([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[S:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[N:46]=[C:45]1[CH2:53][C:54]([O-])=[O:55].[Na+]>C1COCC1.C(Cl)Cl>[S:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[N:46]=[C:45]1[CH2:53][C:54]([NH:11][C@H:8]1[CH2:9][CH2:10][C@@H:5]([N:4]([CH:1]([CH3:3])[CH3:2])[CH3:22])[CH2:6][C@H:7]1[CH2:12][S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:14])=[O:15])=[O:55]
Reactant: O=C([O-])Cc1nc2ccccc2s1
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N)[C@H](CS(=O)(=O)c2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)Cc2nc3ccccc3s2)[C@H](CS(=O)(=O)c2ccccc2)C1
Yield: 60.2 %

Procedure:
A solution of (1R,3R,4S)—N1-isopropyl-N1-methyl-3-(phenylsulfonylmethyl)-cyclohexane-1,4-diamine (see 30b) (70 mg, 0.216 mmol), EDCI (50 mg, 0.260 mmol), HOBT (35 mg, 0.260 mmol), and sodium 2-(benzo[d]thiazol-2-yl)acetate (56 mg, 0.260 mmol) in THF (5 mL) was stirred overnight at room temperature. The mixture was dilute with CH2Cl2 (25 mL) and washed with water, brine and evaporated. The residue was chromatographed on silica gel (6% NH4OH/MeOH/CH2Cl2) to give the product (65 mg). MS found: (M+1)+: 500.49.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[Br:9][C:10]1[CH:22]=[C:21]2[C:13]([C:14]3[CH2:15][CH2:16][CH2:17][C:18](=O)[C:19]=3[N:20]2[CH3:23])=[CH:12][CH:11]=1>CCO.O>[Br:9][C:10]1[CH:22]=[C:21]2[C:13]([C:14]3[CH2:15][CH2:16][CH2:17][C:18](=[N:2][OH:3])[C:19]=3[N:20]2[CH3:23])=[CH:12][CH:11]=1
Reactant: NO
Reactant: Cn1c2c(c3ccc(Br)cc31)CCCC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1c2c(c3ccc(Br)cc31)CCCC2=NO
Yield: 88.4 %

Procedure:
Hydroxylamine hydrochloride (0.56 g, 8.1 mmol) and sodium acetate (0.66 g, 8.1 mmol) were added to a suspension of 7-bromo-9-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (1.5 g, 5.4 mmol) in EtOH (14 mL) and H2O (5.0 mL), and the resulting suspension was heated at reflux for 18 h. The reaction was cooled and concentrated to dryness. The resulting solid was triturated with MeOH (100 mL), and the solids were dried to yield the title compound (1.4 g, 90%) as an off-white powder: 1H NMR (300 MHz, DMSO-d6) δ 11.14 (s, 1H), 7.66 (s, 1H), 7.47 (d, J=8.5 Hz, 1H), 7.15 (dd, J=8.5, 1.0 Hz, 1H), 3.95 (s, 3H), 2.79-2.72 (m, 4H), 1.88-1.83 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1>>[CH3:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][CH2:18][C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=Cc1ccncc1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Product: Cc1ccc(NCc2ccncc2)c(C(=O)O)c1

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from 2-amino-5-methylbenzoic acid (Aldrich) and pyridine-4-carbaldehyde. 13C-NMR (DMSO-d6) δ 169.9, 149.5, 149.1, 148.3, 135.1, 131.5, 123.2, 121.9, 111.7, 110.5, 44.7, 19.6.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9](#N)[CH3:10].[Li].C1C[O:16]CC1>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]([CH3:10])=[O:16])=[CH:3][CH:4]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(Cl)cc1
Reactant: CC#N
Agent: [Li]
Product: CC(=O)c1ccc(C)cc1
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of 126.5 g (1 mol) of p-chlorotoluene and 45.1 g (1.1 mol) of acetonitrile (freshly distilled) is added dropwise to a suspension of 13.8 g (2.0 mol) of lithium granules in 350 ml of THF at −50° C. over the course of 2 hours. After a conversion determined by GC (the dark color of the reaction mixture prevents quantification of lithium consumption) of >98% (overall 7.5 h), the reaction mixture is added to 200 g of water, the pH adjusted to 2.0 using 37% HCl and the reaction mixture boiled for two hours under reflux. The organic phase is then separated off and the aqueous phase extracted once more with 100 ml of petroleum ether. The united organic phases are distilled. 132.7 g (0.99 mol) of 4-methylacetophenone (99%, boiling point 88° C./8 Torr) are obtained as a colorless liquid, GC purity >98% a/a, which when left to stand at RT gradually solidifies.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([NH2:12])[N:9]=[C:8]([NH2:13])[C:7]=1[N+:14]([O-:16])=[O:15].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][N:19]=1.O>N1C=CC=CC=1>[NH2:12][C:10]1[N:9]=[C:8]([NH:13][C:22]([C:21]2[CH:20]=[N:19][C:18]([Cl:17])=[CH:26][CH:25]=2)=[O:23])[C:7]([N+:14]([O-:16])=[O:15])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:11]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1nc(N)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: O
Solvent: c1ccncc1
Product: Nc1nc(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])c(-c2ccco2)n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
A solution of 6-(2-furyl)-5-nitropyrimidine-2,4-diamine (500 mg, 2.26 mmol) in pyridine (10 mL) was treated with 6-chloronicotinoyl chloride (438 mg, 2.49 mmol), stirred for 16 h at 80° C., cooled to room temperature, poured into water (100 mL) and extracted with EtOAc (2×25 mL) and the combined organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; isohexane:EtOAc (3:2)] to give the title compound (430 mg, 82%) as a yellow solid; NMR δH (400 MHz, DMSO) 11.14 (1H, s), 8.86 (1H, d, J 2.5 Hz), 8.27 (1H, dd, J 8.5, 2.5 Hz), 7.93 (1H, m), 7.77 (2H, br s), 7.65 (1H, d, J 7.5 Hz), 7.09 (1H, d, J 4.5 Hz), 6.72-6.70 (1H, m); Retention time 2.41 min.
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][C@H:5]1[CH2:10][O:9][CH2:8][C@@H:7]([C:11]([OH:13])=[O:12])[CH2:6]1>C(OCC)C.CO>[OH:4][C@H:5]1[CH2:10][O:9][CH2:8][C@@H:7]([C:11]([O:13][CH3:3])=[O:12])[CH2:6]1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)[C@@H]1COC[C@H](O)C1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@@H]1COC[C@H](O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of diazomethane in diethyl ether (approx. 0.4 M) is added in excess to a solution of 23 mmol of (cis)-5-hydroxytetrahydropyran-3-carboxylic acid in 300 ml of methanol at 0° C. The mixture is stirred at 0° C. for 2 hours and then quenched with magnesium sulphate, filtered and evaporated. The crude title compound is identified by means of the Rf.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH3:24][O:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[N:29][CH:28]=1>>[CH3:24][O:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:2]([Cl:1])[CH:3]=2)=[N:29][CH:28]=1
Reactant: COC(=O)c1ccc(CBr)nc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Product: COC(=O)c1ccc(COc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)nc1

Procedure:
The title compound was prepared in analogy to Example 93, step 7 from 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (obtained in Example 19, step 5) by alkylation with methyl-6-(bromomethyl)-nicotinate [CAS Reg. No. 131803-48-0]. MS (m/e)=515.0 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:63][C:64]([F:72])([F:71])[CH:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:68]1[CH2:69][CH2:70][CH:65]([C:64]([F:72])([F:71])[F:63])[CH2:66][CH2:67]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: FC(F)(F)C1CCNCC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCC(C(F)(F)F)CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 4-trifluoromethyl-piperidine in DMSO at ambient temperature.
Reaction SMILES: [CH2:1]=O.OS(O)(=O)=O.[NH2:8][CH2:9][CH:10]1[CH2:19]C[C:13]2(OCCO2)[CH2:12][CH2:11]1.[CH3:20][CH2:21][OH:22]>>[N:8]12[CH2:13][CH:12]3[CH2:11][CH:10]([CH2:19][CH:20]([C:21]3=[O:22])[CH2:1]1)[CH2:9]2
Reactant: C=O
Reactant: NCC1CCC2(CC1)OCCO2
Reactant: CCO
Agent: O=S(=O)(O)O
Product: O=C1C2CC3CC1CN(C3)C2
Yield: 69 %

Procedure:
Paraformaldehyde (2.2 g), in 320 ml 2% v/v H2SO4, is heated to boiling and 2.7 g (0.016 mole) of 8-aminomethyl-1,4-dioxaspiro[4,5]decane in 20 ml EtOH, is added over 4 hours. This mixture is then heated at reflux for 24 hours. The cooled reaction is washed with dichloromethane, then basified with 10N NaOH and extracted with dichloromethane. The combined extracts are dried over MgSO4 and stripped to dryness, giving 1.68 g (69%) of product.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:21][NH:22][O:23][CH3:24].N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[CH3:24][O:23][N:22]([CH3:21])[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCc1ccccc1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a solution of 2 g (11.22 mmol) of 5-phenylvaleric acid in 75 mL of CH2Cl2 at 0° C. under argon is added 2 drops of DMF followed by 7 mL (14.03 mmol) of oxalyl chloride. This stirred at 25° C. for 1 hour, then 1.4 g (14.03 mmol) of N,O-dimethylhydroxylamine hydrochloride and 2.7 mL (33.66 mmol, 3 eq) of pyridine are added sequentially and stirred for 72 hours at 25° C. The reaction is partitioned between CH2Cl2 and 1 N HCl. The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo to give 2.5 g (100%) of 5-phenylpentanoic acid-methoxy-methyl-amide in the form of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([N:8]1[C@H:11]([S:12]SC2SC3C=CC=CC=3N=2)[CH2:10][C:9]1=[O:23])=[C:5]([CH3:7])[CH3:6].[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(O)(=O)C.[Zn]>[CH3:1][O:2][C:3](=[O:24])[C:4]([N:8]1[C@H:11]([S:12][C:25](=[O:27])[CH3:26])[CH2:10][C:9]1=[O:23])=[C:5]([CH3:6])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C(=C(C)C)N1C(=O)C[C@H]1SSc1nc2ccccc2s1
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)C(=C(C)C)N1C(=O)C[C@H]1SC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 g of zinc powder is added in portions over a period of one hour to a solution, stirred under nitrogen and in an ice bath, of 380 mg (1 mmol) of 2-[(4R)-4-(benzthiazol-2-yl-dithio)-2-oxoazetidin-1-yl]-3-methylcrotonic acid methyl ester in 3 ml of acetic anhydride and 5 ml of glacial acetic acid. The reaction mixture is further stirred for one hour at room temperature, filtered and concentrated in vacuo. The residue is taken up in methylene chloride and washed in succession with 25% aqueous ammonium chloride solution and aqueous sodium bicarbonate solution. The combined aqueous phases are re-extracted with methylene chloride, all the methylene chloride phases are combined, dried with sodium sulphate and concentrated in vacuo. The residue is chromatographed over 40 g of silica gel (deactivated with 10% water) with toluene and toluene/ethyl acetate (19:1) and yields the optically pure title compound having a melting point of 78°-80°;
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:10]=[CH:9][O:8][C:7]=1[CH3:11])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:11][C:7]1[O:8][CH:9]=[CH:10][C:6]=1[CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)Cc1ccoc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1occc1CCO
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of (2-methyl-furan-3-yl)-acetic acid ethyl ester (11.8 g, 70.2 mmoles) in tetrahydrofuran (50 ml) was added to a stirred suspension of lithium aluminium hydride (2.66 g, 70.2 mmoles) under a nitrogen atmosphere and with cooling to 0° C. When the addition was complete the mixture was stirred at room temperature for 3 hours, then quenched by the addition of excess acetone. After acidifying with 10% aqueous hydrochloric acid the mixture was extracted three times with diethyl ether. The combined extracts were dried and evaporated to afford crude 2-(2-methyl-furan-3-yl)-ethanol as a yellow oil. (ii) Compound (70) was prepared in the form of a pale yellow oil from crude 2-(2-methyl-furan-3-yl)-ethanol (from (i)) by adapting the procedure of Example 1(a).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10][CH3:11])[CH:5]=O.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C-:30]#[N:31].[K+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:30]#[N:31])[CH:7]=[CH:8][C:9]=1[S:10][CH3:11]
Reactant: C1COCCN1
Reactant: CSc1ccc(C=O)cc1Cl
Reactant: [C-]#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(C(C#N)N2CCOCC2)cc1Cl
Yield: 95 %

Procedure:
To a solution of 3-chloro-4-(methylsulfanyl)benzaldehyde (12.3 g) in tetrahydrofuran (50 mL) were added morpholine (13.4 mL), p-toluenesulfonic acid monohydrate (10.8 g) and a solution of potassium cyanide (4.50 g) in water (10 mL), and the mixture was heated under reflux for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from hexane-ethyl acetate to give the title compound (14.0 g, yield 95%) as colorless crystals.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([NH2:15])[C:6]1[CH:14]=[CH:13][C:12]2[O:11][CH2:10][O:9][C:8]=2[CH:7]=1.CCN(C(C)C)C(C)C.Cl.[NH2:26][C:27]1[S:28][CH:29]=[C:30]([CH2:32][Cl:33])[N:31]=1>C1(C)C=CC=CC=1.C1COCC1>[O:11]1[C:12]2[CH:13]=[CH:14][C:6]([CH2:5][NH:15][C:1]([NH:26][C:27]3[S:28][CH:29]=[C:30]([CH2:32][Cl:33])[N:31]=3)=[O:2])=[CH:7][C:8]=2[O:9][CH2:10]1
Reactant: O=C(Cl)Cl
Reactant: Nc1nc(CCl)cs1
Reactant: NCc1ccc2c(c1)OCO2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc2c(c1)OCO2)Nc1nc(CCl)cs1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 32 %

Procedure:
Phosgene (54.0 mmol, 27.9 mL of a 1.93 M solution in toluene) was placed in a 3-neck-flask and cooled to 0° C. THF (10 mL) was added, followed by a mixture of piperonylamine (27.0 mmol, 4.0 g) and DIPEA (56.7 mmol, 7.3 g) in THF (20 mL) at 0° C. After complete addition the mixture was stirred for another 40 min at 0° C. The reaction mixture was then concentrated. To the crude material THF (40 mL) and DIPEA (4.4 mL) were added. This mixture was then added to a slurry of 2-amino-4-(chloromethyl)thiazole hydrochloride (24.3 mmol, 4.5 g) in THF (50 mL). After stirring for 72 h at room temperature the reaction mixture was filtered through celite. The celite was washed with ethylacetate. The combined filtrate was concentrated and the material was directly applied to column chromatography (MeOH/DCM) providing 2.6 g (32%) of the desired intermediate. 1H-NMR (CD3OD, 300 MHz) δ 6.96 (s, 1H), 6.79 (m, 3H), 5.91 (s, 2H), 4.55 (s, 2H), 4.32 (s, 2H).