Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[CH:10]([CH:11]2[CH2:13][CH2:12]2)[CH2:9][N:8]=[C:7](OC)[C:6]1=[O:16].[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[C:31]([NH:33][NH2:34])=O>C(O)CCC>[Cl:1][C:2]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[CH:10]([CH:11]2[CH2:13][CH2:12]2)[CH2:9][N:8]2[C:31]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][N:25]=3)=[N:33][N:34]=[C:7]2[C:6]1=[O:16]
Reactant: COC1=NCC(C2CC2)N(Cc2cccc(C(F)(F)F)c2Cl)C1=O
Reactant: NNC(=O)c1cnccn1
Solvent: CCCCO
Product: O=C1c2nnc(-c3cnccn3)n2CC(C2CC2)N1Cc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Yield: 44.6 %

Procedure:
A solution of (±)-1-(2-chloro-3-(trifluoromethyl)benzyl)-6-cyclopropyl-3-methoxy-5,6-dihydropyrazin-2(1H)-one (216 mg, 0.58 mmol) and pyrazine-2-carbohydrazide (88 mg, 0.63 mmol) in 1-butanol (5.8 mL) was heated at 130° C. for 16 h. After cooling to rt, the solvent was removed in vacuo. Purification by chromatography (SiO2; hexanes—100% EtOAc) afforded the desired product as a white solid (116 mg, 45%). MS (ESI): mass calcd. for C20H16ClF3N6O, 448.1; m/z found, 449.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.69-9.58 (m, 1H), 8.70 (d, J=2.6 Hz, 1H), 8.64 (dd, J=2.5, 1.5 Hz, 1H), 7.75-7.62 (m, 2H), 7.38 (t, J=7.8 Hz, 1H), 5.49 (d, J=15.9 Hz, 1H), 5.27-5.16 (m, 1H), 4.78 (dd, J=15.6, 1.7 Hz, 1H), 4.68 (ddd, J=13.9, 4.5, 2.4 Hz, 1H), 3.16 (ddd, J=9.9, 4.5, 3.3 Hz, 1H), 1.06-0.96 (m, 1H), 0.80-0.72 (m, 1H), 0.67-0.43 (m, 2H), 0.28-0.21 (m, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:23][CH2:24][CH3:25])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[CH:26](O)=[O:27].C(OC(=O)C)(=O)C>O1CCCC1>[CH2:24]([O:23][C@@H:19]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([NH:2][CH:26]=[O:27])=[CH:8][CH:7]=2)=[CH:13][CH:14]=1)[C:20]([OH:22])=[O:21])[CH3:25]
Reactant: O=CO
Reactant: CCO[C@@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NC=O)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
3-{4-[2-(4-Aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride (described in Example 56a) (0.115 g, 0.314 mmole) in tetrahydrofuran (3 ml) was mixed with a mixture of formic acid (0.5 ml) and acetic anhydride (0.3 ml). The resulting mixture was stirred at room temperature overnight. Tetrahydrofuran was evaporated. Ethyl acetate and water were added into the residue. The phases were separated. The organic phase was washed with brine, dried with magnesium sulfate and the solvent was evaporated. Chromatography of the residue on silica gel (Isolute, SI) using dichloromethane, then methanol/dichloromethane (1%), followed by methanol/dichloromethane (2%) as eluants gave 0.07 g (yield 62%) of (S)-2-ethoxy-3-(4-{[4-(formylamino)phenethyl]oxy}phenyl)propanoic acid.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:53](=[O:56])[CH:54]=[CH2:55])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].C[Si](C)(C)[O:59][C:60]1[CH2:64][CH2:63][CH2:62][CH:61]=1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:53](=[O:56])[CH2:54][CH2:55][CH:61]3[CH2:62][CH2:63][CH2:64][C:60]3=[O:59])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)OC1=CCCC1
Reactant: C=CC(=O)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c(=O)c2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCc1nc2ccc(C(=O)CCC3CCCC3=O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.201 g of the product of Example 3 in 4.5 ml of methylene chloride, cooled to -78° C., is added dropwise 0.549 ml of 1.0M TiCl4 in methylene chloride. The reaction mixture is stirred at -78° C. for 30 minutes and 0.098 ml of 1-(trimethylsilyloxy)-cyclopentene added dropwise. The reaction mixture is stirred at -78° C., for 0.5 hours and quenched with saturated potassium carbonate, diluted with chloroform, filtered through magnesium sulfate and concentrated in vacuo to give a residue which is purified by chromatography on silica gel by elution with 1:3 ethyl acetatehexane to give 0.079 g of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10](=O)[CH3:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl.[NH2:25][OH:26]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10](=[N:25][OH:26])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)N1CCCC1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NO)C(Cc1ccc(Cl)cc1)N1CCCC1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-chlorophenyl)-3-pyrrolidin-N-yl-butan-2-one (200 mg, 0.79 mmol, from Step B) dissolved in ethanol (2 mL), was added pyridine (63 mg, 0.79 mmol), and hydroxylamine hydrochloride (78 mg, 1.12 mmol). The mixture was refluxed for 24 h when LC/MS indicated disappearance of all starting material. The mixture was cooled to room temperature, concentrated under reduced pressure, treated with 33% aqueous potassium carbonated, and extracted with chloroform 5 times. The organic layers were combined and filtered over glass wool and dried over potassium carbonate. The filtrated obtained after passing through sintered glass was concentrated to give the oxime, homogeneous by TLC, Rf=0.3 in 95:5 CH2Cl2: MeOH. LC/MS m/e=267 (M+1). 500 MHz 1H NMR (CDCl3) δ 1.73 (m, 4H), 1.76 (s, 3H), 2.40 (m, 2H), 2.60 (m, 2H), 2.72 (dd, J=2.7, 10.8 Hz, 1H), 2.94 (dd, J=4.3, 8.8 Hz, 1H), 3.03 (dd, J=4.4, 13.3 Hz, 1H), 3.8 (s, 1H), 6.96 (d, J=8.3 Hz, 2H), 7.11 (d, J=8.3 Hz, 2H)
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:14]=[C:15]([CH2:19][CH2:20][NH2:21])[CH:16]=[CH:17][CH:18]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([C@@H:41]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:42]Br)=[C:34]2[C:39]=1[NH:38][C:37](=[O:40])[CH:36]=[CH:35]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+].[I-].[Na+]>CS(C)=O.O>[C:1]12([CH2:11][O:12][C:13]3[CH:14]=[C:15]([CH2:19][CH2:20][NH:21][CH2:42][C@@H:41]([C:33]4[CH:32]=[CH:31][C:30]([O:29][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[C:39]5[C:34]=4[CH:35]=[CH:36][C:37](=[O:40])[NH:38]5)[O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH:16]=[CH:17][CH:18]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NCCc1cccc(OCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1cccc(OCC23CC4CC(CC(C4)C2)C3)c1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a solution of Intermediate 41 (0.117 g, 0.41 mmol) in dimethyl sulfoxide (0.8 mL) and a solution of (R)-8-(benzyloxy)-5-(2-bromo-1-(tert-butyldimethylsilyloxy)-ethyl)quinolin-2(1H)-one (0.2 g, 0.41 mmol) in dimethyl sulfoxide (0.8 mL) was added sodium hydrogen carbonate (0.103 g, 1.23 mmol) and sodium iodide (0.092 g, 0.61 mmol). The resulting reaction mixture was stirred at 150° C. for 1 hour. The mixture was poured into water and the precipitate was collected by filtration and washed with ether and ethyl acetate. The title compound was obtained as a brown solid (0.231 g, 57%) and was used in the next step without further purification. MS (M+): 694.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH2:12]([C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)[CH2:13][CH3:14]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([N:16]2[CH:17]=[CH:18][N:19]=[C:15]2[CH2:12][CH2:13][CH3:14])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CCCc1ncc[nH]1
Solvent: CN(C)C=O
Product: CCCc1nccn1-c1nc(Cl)nc2nc[nH]c12
Temperature: 65 °C
Reaction time: 20 h
Yield: 72.3 %

Procedure:
2,6-Dichloropurine (0.38 g, 2 mmol) and 2-propylimidazole (1.32 g, 12 mmol) were dissolved in freshly distilled DMF (10 mL), and the mixture was stirred at 65° C. for 20 h. Volatiles were evaporated in vacuo, and the residue was dissolved in 0.1 N NaOH/H2O//CH2Cl2 (100 mL/50 mL). The organic phase was extracted with 0.1 N NaOH/H2O (3×50 mL). The combined aqueous phase was washed with CH2Cl2 (2×50 mL) and neutralized with CO2. The precipitated solid was filtered and washed (H2O) to give 2-chloro-6-(2-propylimidazol-1-yl)purine (0.38 g, 72%): mp 224.5-225° C.; UV (MeOH) max 215, 288 nm (∈ 25 800, 16 700), min 332, 241 nm (∈ 2500, 4500); 1H NMR (500 MHz, DMSO-d6) δ 14.04 (br s, 1H), 8.69 (s, 1H), 8.43 (s, 1H), 7.06 (s, 1H,), 3.12 (t, J=7.5 Hz, 2H), 1.72 (sext, J=7.3 Hz, 2H), 0.95 (t, J=7.3 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ 157.3, 151.7, 150.2, 147.2, 146.6, 128.9, 122.5, 121.1, 32.4, 21.5, 14.5; HRMS m/z 262.0723 (M+[C11H11ClN6]=262.0734). Anal. Calcd for C11H11ClN6: C, 50.29; H, 4.22; N, 31.99. Found: C, 50.02; H, 4.28; N, 31.64.
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]1(=[O:14])[CH2:13][CH2:12][CH:11]=[CH:10]1.CN(C1CCCCC1)C1CCCCC1>O1CCOCC1.CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:8][C:3]1[C:2]([C:11]2[CH2:12][CH2:13][C:9](=[O:14])[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C1C=CCC1
Reactant: Fc1ncccc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1C=C(c2cccnc2F)CC1
Temperature: 23 °C
Reaction time: 21 h

Procedure:
A solution of 3-bromo-2-fluoropyridine (4 g, 22.73 mmol), 2-cyclopenten-1-one (7.35 mL, 91 mmol), n-methyldicyclohexylamine (12.05 mL, 56.8 mmol) and bis(tri-tert-butylphosphine)palladium (0) (0.581 g, 1.136 mmol) in 1,4-dioxane (50 mL) was heated to 105° C. in a capped vessel. After 21 h, the reaction was cooled to 23° C., diluted with EtOAc (400 mL) and washed with water (150 mL) and brine (150 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 15-50% EtOAc/hexane), affording the product as a yellow solid. MS (ESI, pos. ion) m/z: 178.0 (M+1).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]2[CH2:22][CH2:21]2)[C:13]=1[C:14]#[N:15].C(N(CC)CC)C>C(Cl)Cl.N1C=CC=CC=1>[C:14]([C:13]1[C:16]([CH:20]2[CH2:22][CH2:21]2)=[CH:17][CH:18]=[CH:19][C:12]=1[NH:11][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])#[N:15]
Reactant: N#Cc1c(N)cccc1C1CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1c(NS(=O)(=O)c2ccccc2)cccc1C1CC1
Reaction time: 5 h
Yield: 39.4 %

Procedure:
Benzenesulfonyl chloride (0.093 g) was added to a solution of 2-amino-6-cyclopropyl-benzonitrile (Intermediate 10, 0.07 g) in DCM (4 mL) and pyridine (0.1 mL). The mixture was stirred for 5 hours, then a further aliquot of benzenesulfonyl chloride (0.093 g) was added together with triethylamine (0.12 mL) and the mixture was stirred overnight. The reaction mixture was washed with water, and the organic solution was dried with magnesium sulfate, filtered and the filtrate was evaporated under vacuum. The residue was purified by flash chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane. The fractions containing the desired product were combined and evaporated to give the title compound as a colorless oil (0.052 g).
Reaction SMILES: [BH3-]C#N.[Na+].Cl.[NH2:6][C:7]1[NH:11][CH:10]=[N:9][C:8]=1[C:12]([NH2:14])=[O:13].C(O)(=O)C.[CH2:19]([O:21][C:22]([CH3:26])([CH3:25])[CH:23]=O)[CH3:20]>CO>[CH2:19]([O:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH:6][C:7]1[N:11]=[CH:10][NH:9][C:8]=1[C:12]([NH2:14])=[O:13])[CH3:20]
Reactant: NC(=O)c1nc[nH]c1N
Reactant: CCOC(C)(C)C=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(C)(C)CNc1nc[nH]c1C(N)=O
Temperature: 25 °C
Yield: 90 %

Procedure:
NaCNBH3 (0.077 g, 1.23 mmol) was added to 5-amino-4-imidazolecarboxamide hydrochloride (0.200 g, 1.23 mmol) and acetic acid (141 μL, 2.46 mmol) in methanol (1.5 mL). 2-Ethoxy-2-methylpropanal (0.286 g, 2.46 mmol) obtained from Example 1(b) was added drop by drop. After 1.5 h more 2-Ethoxy-2-methylpropanal (0.300 g, 2.58 mmol) was added followed by more 2-Ethoxy-2-methylpropanal after 0.5 h (0.424 mg, 3.65 mmol). The reaction mixture was stirred at r.t. 17 h after which it was concentrated and purified by flash silica gel chromatography (CHCl3/MeOH; 20:1-9.1), to give the title compound as an oil in 90% yield (0.251 g). MS (ESI) m/z 227 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[NH2:22])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.O.[N:24]#[C:25][Br:26]>C(#N)C>[BrH:26].[NH2:24][C:25]1[NH:22][C:21]2[CH:20]=[CH:19][C:4]([O:5][CH:6]3[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]3)=[CH:3][C:2]=2[N:1]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)c(N)c2)CC1
Reactant: N#CBr
Solvent: O
Solvent: CC#N
Product: Br
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3[nH]c(N)nc3c2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
tert-Butyl 4-(3,4-diaminophenoxy)piperidine-1-carboxylate (5.673 mmoles, 1.914 g, 1 equivalent) was dissolved in acetonitrile (20 ml) and water (20 ml) and cooled to 0-5° C. (ice-water). Cyanogen bromide (5.67 mmoles, 0.721 g, 1.4 equivalents) was added in one lot and the reaction mixture was allowed to go to room temperature and stirred for 16 hours. The reaction mixture was then evaporated under reduced pressure to 2.41 g of tert-butyl 4-(2-amino-1H-benzo[d]imidazol-5-yloxy)piperidine-1-carboxylate hydrobromide (yield: 100%) which was used directly in the next reaction without any further purification. 1H-NMR (400 MHz, DMSO-d6) δ 12.22 (br s, 2H), 8.39 (s, 2H), 7.22 (d, 1H), 6.91 (s, 1H), 7.83 (d, 1H), 4.50 (m, 1H), 3.61 (m, 2H), 2.19 (, 2H), 1.90 (m, 2H), 1.40 (s, 9H). MS (EI): 333 (MH+).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH3:13])[CH:10]1[O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([Mg]Cl)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:1]([O:8][C@H:9]([CH:10]([OH:12])[CH2:11][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](OCc1ccccc1)C1CO1
Reactant: Cl[Mg]CCc1ccccc1
Product: C[C@H](OCc1ccccc1)C(O)CCCc1ccccc1

Procedure:
(2S)-2-benzyloxy-6-phenylhexan-3-ol was prepared from (3S)-3-benzyloxy-1,2-epoxybutane (obtained in Preparation 9) and phenethylmagnesium chloride.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([N:7]=[C:8]=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.[OH:16][CH2:17][CH2:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][C:22](=[O:28])[NH:23]2>O1CCCC1.CN(C)C=O.N1C=CC=CC=1>[O:28]=[C:22]1[CH2:21][C:20]2[C:24](=[CH:25][CH:26]=[CH:27][C:19]=2[CH2:18][CH2:17][O:16][C:8](=[O:9])[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:23]1
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: O=C=Nc1ccccc1-c1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C1Cc2c(CCOC(=O)Nc3ccccc3-c3ccccc3)cccc2N1
Temperature: 80 °C
Yield: 79.7 %

Procedure:
2-Biphenylyl isocyanate (1.15 mL, 6.7 mmol) was added dropwise to a stirred mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (709 mg, 4 mmol) in tetrahydrofuran (8 mL), dimethylforamide (2 mL) and pyridine (3 drops) under nitrogen atmosphere. The mixture was heated at 80° C. for 15 hours. The reaction was cooled, quenched with 1 N sodium hydroxide solution (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate:hexane 3:2 to give 1.188 g (80%) of biphenyl-2-yl-carbamic acid 2-(2-oxo-2,3-dihydro-1H-indol-4-yl)-ethyl ester as a white fluffy solid.
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C:7]1[C:8]2[N:9]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:10]=[C:11]([C:13]([NH2:15])=[O:14])[CH:12]=1.Cl[CH2:22][C:23]1[C:24]([CH3:29])=[CH:25][CH:26]=[CH:27][CH:28]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:19][C:17]1[N:18]=[C:8]2[C:7]([NH:6][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:12][C:11]([C:13]([NH2:15])=[O:14])=[CH:10][N:9]2[C:16]=1[CH3:20]
Reactant: Cc1nc2c(N)cc(C(N)=O)cn2c1C
Reactant: Cc1ccccc1CCl
Agent: CS(=O)(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1CNc1cc(C(N)=O)cn2c(C)c(C)nc12
Yield: 13.2 %

Procedure:
8-Amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide mesylate (1.0 g, 2.7 mmol), α-chloro-o-xylene (0.38 g, 2.7 mmol) and diisopropylethylamin (0.76 g, 5.9 mmol) in dimethylformamide (7 ml) were stirred at 50° C. for 7 h and at room temperature for 72 h. The solvent was evaporated and the residue was treated with a mixture of methylene chloride, water and a small amount of diisopropylethylamin. The solid that formed was isolated by filtration and washed with ethylacetate to give 0.11 g (13%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O.C([Cl:20])(=O)C>>[Cl-:20].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[N+:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: C1COCCN1
Reactant: COc1ccccc1C=O
Product: COc1ccccc1C=[N+]1CCOCC1
Product: [Cl-]

Procedure:
The reaction of 18.8 ml (0.216 mol) morpholine and 12.4 g (0.09 mol) 2-methoxybenzaldehyde in accordance with general synthesis instructions 2 and subsequent reaction with 5.3 ml (0.110 mol) acetyl chloride in accordance with general synthesis instructions 3 gave 7.61 g (corresponding to 38% of the yield calculated by theory) 4-(2-methoxy-benzylidene)-morpholin-4-ium chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Cl:10][CH2:11][CH2:12][N:13]=[C:14]=[O:15]>O1CCOCC1>[Cl:10][CH2:11][CH2:12][NH:13][C:14]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1)=[O:15]
Reactant: O=C=NCCCl
Reactant: N#Cc1cccc(N)c1
Solvent: C1COCCO1
Product: N#Cc1cccc(NC(=O)NCCCl)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
65.00 g (550 mmol) 3-amino-benzonitrile are dissolved in 450 ml dioxane, 56 ml (660 mmol) 1-chloro-2-isocyanato-ethane dissolved in 60 ml dioxane are added dropwise. The reaction mixture is stirred for 3 hours at 60° C. and for 16 hours at ambient temperature. Then the precipitate is suction filtered, washed with diethyl ether and dried.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]1)(=[O:20])=[O:19]
Reactant: OCCN1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(CCO)CC1
Temperature: 0 °C
Yield: 480.1 %

Procedure:
2-Piperazin-1-yl-ethanol (1.30 g, 1.0 mmol) and triethylamine (2.8 mL, 2 mmol) were dissolved in methylene chloride (20 mL). The solution was cooled to 0° C. and methanesulfonyl chloride (0.78 mL, 1 mmol) was added dropwise. The mixture was warmed to r.t., and the solvent was removed under reduced pressure. The residue was purified via silica gel chromatography (10% methanol in ethyl acetate) to afford the title compound (1.0 g, 48%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH:9]([C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:12]=2)O)[CH:2]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[CH:12]1[C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=2[CH:19]=[CH:20][C:11]=1/[CH:9]=[CH:8]/[CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1.[CH:12]1[C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=2[CH:19]=[CH:20][C:11]=1/[CH:9]=[CH:8]\[CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: OC(CCc1cccnc1)c1ccc2c(c1)CCCC2
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C(=C/c1ccc2c(c1)CCCC2)\Cc1cccnc1
Product: C(=C\c1ccc2c(c1)CCCC2)\Cc1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled (0° C.) solution of 3-(3-pyridyl)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)propanol (2.29 g) in CH2Cl2 (50 ml) were added triethylamine (2.4 ml) and methanesulfonyl chloride (0.86 ml ). The mixture was stirred at room temperature for 16 hours. The mixture was washed with water and brine, dried and concentrated. The residue was mixed with 1,8-diazabicyclo[5.4.0]undec-7-ene (2.59 g) and stirred at 100° C. for 45 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried and concentrated. The residue was chromatographed on silica gel (hexane-ethyl acetate=3:1) to give 3-[(E)-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-propen-1-yl]pyridine (216 mg) and 3-[(Z)-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-propen-1-yl]pyridine (245 mg). 3-[(E)-(5,6,7,8-Tetrahydronaphthalen-2-yl)-2-propen-1-yl]pyridine
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH:21]1[CH2:30][CH2:31][OH:32])=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:33]1(O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH:21]1[CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: Oc1ccccc1
Reactant: COC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCOc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.7 %

Procedure:
A solution of diethyl azodicarboxylate (0.74 ml, 4.7 mmol) in anhydrous dichloromethane (3 ml) was added to a stirred, ice-methanol cooled solution of (RS)-1-(tert-butoxycarbonyl)-2-(2-hydroxyethyl) -4-methoxycarbonylpiperazine (D7) (1.35 g, 4.69 mmol), phenol (0.441 g, 4.69 mmol) and triphenylphosphine (1.23 g, 4.69 mmol) in anhydrous dichloromethane (40 ml). The mixture was stirred at room temperature for 18 h then evaporated in vacuo. The residue was chromatographed on silica gel eluting with 10-20% ethyl acetate in hexane to give the title compound (1.43 g, 84%). 1H NMR (CDC13) δ: 1.38 (9H, m), 1.85-2.20 (2H, m), 2.75-3.20 (3H, m), 3.72 (3H, s), 3.80-4.20 (5H, m), 4.39 (1H, broad m), 6.75-7.00 (3H, m), 7.15-7.35 (2H, m).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])=[N:5][C:6]([S:10][CH3:11])=[N:7][C:8]=1[Cl:9].[C:21](C1NC=CN=1)(C1NC=CN=1)=[O:22]>C(Cl)Cl>[Cl:9][C:8]1[N:7]=[C:6]([S:10][CH3:11])[N:5]=[C:4]2[N:12]([C:13]3[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=3[F:19])[C:21](=[O:22])[NH:1][CH2:2][C:3]=12
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CSc1nc(Cl)c(CN)c(Nc2c(F)cccc2F)n1
Solvent: ClCCl
Product: CSc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 81.3 %

Procedure:
To the solution of 5-(aminomethyl)-6-chloro-N-(2,6-difluorophenyl)-2-(methylthio)-4-pyrimidinamine (0.317 g) in CH2Cl2 (5 mL) was added the mixture of carbonyl diimidazole (0.178 g) in CH2Cl2 (5 mL). The resultant mixture was stirred for about 3 hours at r.t., mixed with CH2Cl2 (10 mL) and washed with HCl (1 N, 2×10 mL) and H2O (20 mL). The organic layers were collected, dried over Na2SO4, filtered and concentrated to provide the title compound (0.279 g, 81%). LC-MS m/z 343 (M+H)+, 1.75 min (ret. time); 1H-NMR (400 MHz, CDCl3) δ 7.44-7.40 (m, 1H), 7.07-7.03 (m, 2H), 5.84 (br, 1H), 4.62 (s, 2H), 2.19 (s, 3H).