Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:17][CH:18]1[O:22][CH:21]([CH3:23])[CH:20]([CH3:24])[O:19]1>>[CH3:24][CH:20]1[CH:21]([CH3:23])[O:22][CH:18]([CH2:17][NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[O:2][CH3:1])[O:19]1
Reactant: CC1OC(CBr)OC1C
Reactant: COc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccccc1NCC1OC(C)C(C)O1
Temperature: 100 °C

Procedure:
2-Methoxyaniline (87 ml; 0.7 mole) and sodium carbonate (31.66 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Bromomethyl-4,5-dimethyl-1,3-dioxolane (25 mls) was added and the reaction mixture was heated at a temperature of 100° C. for a period of about 4 hours. After this time the reaction mixture was filtered and additional sodium carbonate (5.00 grams) was added to the filtrate. The mixture was then distilled under reduced pressure to yield the desired product N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)-2-methoxyaniline boiling at 125° to 128° C. at 0.1 mm of Hg pressure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([SH:8])[CH:7]=1.[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18](F)=[C:17]([Cl:22])[CH:16]=1)(=[O:14])=[O:13]>>[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([S:8][C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:9][CH3:10])=[C:17]([Cl:22])[CH:16]=1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: COc1ccc(F)cc1S
Product: COc1ccc(F)cc1Sc1ccc(S(C)(=O)=O)cc1Cl

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (ii) and the product from example 7 step (ii), yield 0.8 g.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:3][CH:2]1[C:4](O)=[O:5].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([N:17]1[C:7](=[O:9])[CH:1]2[CH:2]([CH2:3]2)[C:4]1=[O:5])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)C1CC1C(=O)O
Reactant: NCc1ccccc1
Product: O=C1C2CC2C(=O)N1Cc1ccccc1

Procedure:
1,2-cyclopropanedicarboxylic acid is treated with benzylamine to form 3-(benzyl)-3-azabicyclo(3.1.0)hexane-2,4-dione (I).
Reaction SMILES: [CH:1]1([C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)([O:8][CH3:9])[CH2:5][CH:6]=[CH2:7])[CH2:3][CH2:2]1.ClC1C=C(C(OO)=[O:25])C=CC=1>ClCCl>[CH:1]1([C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)([O:8][CH3:9])[CH2:5][CH:6]2[CH2:7][O:25]2)[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC(OC)(c1ccc(F)cc1)C1CC1
Solvent: ClCCl
Product: COC(CC1CO1)(c1ccc(F)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 100.6 parts of 1-(1-cyclopropyl-1-methoxy-3-butenyl)-4-fluorobenzene and 238 parts of dichloromethane was added a solution of 101.5 parts of 3-chlorobenzeneperoxoic acid in 952 parts of dichloromethane (exothermic reaction after 30 minutes). The whole was stirred overnight at room temperature. The precipitate was filtered off and the filtrate was washed successively with a saturate sodium carbonate solution, a saturate sodium sulfite solution, a 5% sodium hydroxide solution and water. The organic phase was dried, filtered and evaporated, yielding 106 parts of [2-cyclopropyl-2-(4-fluorophenyl)-2-methoxyethyl]oxirane as a residue (intermediate 7).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8](=[O:16])[C@@H:9]([NH:12][C:13](=[O:15])[CH3:14])[CH2:10][OH:11])=[CH:4][CH:3]=1.[Si]([N:23]=[N+:24]=[N-])(C)(C)C>>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:16])[C@@H:9]([NH:12][C:13](=[O:15])[CH3:14])[CH2:10][OH:11])=[CH:17][CH:18]=1)=[N+:23]=[N-:24]
Reactant: CC(=O)N[C@@H](CO)C(=O)NCc1ccc(N)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Product: CC(=O)N[C@@H](CO)C(=O)NCc1ccc(N=[N+]=[N-])cc1
Yield: 92.1 %

Procedure:
Using (S)—N-(4-aminobenzyl)-2-acetamido-3-hydroxypropanamide (2.80 g, 11.16 mmol), t-BuONO (3.98 mL, 33.48 mmol), TMSN3 (3.52 mL, 26.78 mmol), and the preceding procedure gave 2.85 g (92%) of (S)—N-(4-azidobenzyl)-2-acetamido-3-hydroxypropanamide as a white solid: mp 161-162° C.; [α]26D −13.6° (c 1.0, MeOH); Rf=0.35 (1/9 MeOH/CHCl3); IR (nujol mull) 3267, 2924, 2129, 1648, 1552, 1459 cm−1; 1H NMR (DMSO-d6) δ 1.87 (s, CH3C(O)), 3.58 (t, J=5.6 Hz, CH2OH), 4.26-4.31 (m, CH2Ar and CH), 4.91 (t, J=5.6 Hz, OH), 7.03-7.08 (m, 2 ArH), 7.27-7.32 (m, 2 ArH), 7.94 (d, J=7.8 Hz, NHCH), 8.40 (t, J=6.0 Hz, NHCH2); 13C NMR (DMSO-d6) δ 22.6 (CH3C(O)), 41.5 (CH2Ph), 55.3 (CH), 61.7 (CH2OH), 118.9, 128.7, 136.5, 137.7 (C6H5), 169.4, 170.3 (2 C(O)); HRMS (ESI) 278.1248 [M+H+] (calcd. for C12H16N5O3 278.1253); Anal. (C12H15N5O3) Calcd.: C, 51.98%; H, 5.45%; N, 25.26%. Found: C, 52.08%; H, 5.51%; N, 25.00%.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[CH2:10]([O:12][C:13](=[O:19])[C:14](OCC)=[O:15])[CH3:11].CC[O-].[Na+]>>[CH2:10]([O:12][C:13](=[O:19])[C:14](=[O:15])[CH2:7][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][CH:2]([CH3:9])[CH3:1])[CH3:11]
Reactant: CC(=O)CCCC(C)C
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)CC(=O)CCCC(C)C
Temperature: 25 °C
Yield: 46.8 %

Procedure:
6-Methyl-2-heptanone (0.9981 g, 7.80 mmol) and diethyloxalate (1.06 mL, 7.80 mmol) were mixed together, and then added to a solution of NaOEt (˜3 M, 2.6 mL) stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred overnight. The reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, and concentrated to yield crude 16. The crude material was purified with 1:1 Hexanes: CH2Cl2 to obtain 0.8342 g (46.9%) of 16. 1H (CD3OD, 400 MHz): δ 6.36 (1H, s), 4.30 (2H, q, J=7.1 Hz), 2.50 (2H, t, J=7.3 Hz), 1.68-1.59 (2H, m), 1.61-1.50 (1H, m), 1.33 (3H, t, J=7.1 Hz), 1.25-1.17 (2H, m), 0.89 (6H, d, J=7.0 Hz) ppm. 13C (CD3OD, 100 MHz): δ 204.41, 166.93, 163.28, 102.66, 63.29, 41.89, 39.41, 28.92, 23.65, 22.89, 14.33 ppm.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.C1(CC([NH:16][CH:17]2[C:45](=[O:46])[N:19]3[C:20]([C:29]([O:31][CH:32]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])=[C:21]([CH2:24][S:25][CH2:26][CH:27]=[CH2:28])[CH2:22][S:23][C@H:18]23)=O)C=CC=CC=1.C(=O)(O)[O-].[Na+].C(OC(C)C)(C)C>C(Cl)Cl.O.CO.N1C=CC=CC=1>[NH2:16][CH:17]1[C:45](=[O:46])[N:19]2[C:20]([C:29]([O:31][CH:32]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[O:30])=[C:21]([CH2:24][S:25][CH2:26][CH:27]=[CH2:28])[CH2:22][S:23][C@H:18]12
Reactant: C=CCSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Temperature: -20 °C
Yield: 37.3 %

Procedure:
To a suspension of phosphorus pentachloride (16.1 g) and pyridine (6.3 ml) in methylene chloride (100 ml) were added benzhydryl 7-(2-phenylacetamido)-3-allylthiomethyl-3-cephem-4-carboxylate (22 g) and methylene chloride (100 ml) at 5° C., and the mixture was stirred at the same temperature for an hour. After cooling to -20° C., methanol (10 ml) was added thereto, followed by stirring at -10° C. for half an hour. To this mixture was added water (10 ml) and stirred for 10 minutes. To the separated methylene chloride was added an aqueous solution of sodium bicarbonate until the pH value of the aqueous solution became 5.0, and the mixture was shaken. After separating out the organic layer, it was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue obtained was pulverized with diisopropyl ether to give benzhydryl 7-amino-3-allylthiomethyl-3-cephem-4-carboxylate (6.5 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9](=[O:21])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[C:7]1[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=1[S:5]2.[CH3:26][O:27][CH2:28][CH2:29][O:30][C:31]1[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O.[O-]CC.[Na+]>C(O)C>[CH3:26][O:27][CH2:28][CH2:29][O:30][C:31]1[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:32]=1/[CH:33]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:5][C:6]3[CH:25]=[CH:24][CH:23]=[CH:22][C:7]=3[N:8]2[C:9](=[O:21])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=1
Reactant: Cc1nc2sc3ccccc3n2c(=O)c1-c1ccc(C(F)(F)F)cc1
Reactant: COCCOc1c(C=O)cccc1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COCCOc1c(/C=C/c2nc3sc4ccccc4n3c(=O)c2-c2ccc(C(F)(F)F)cc2)cccc1OC
Yield: 46.7 %

Procedure:
The title compound was synthesized by condensation of Intermediate 23 (250 mg, 0.690 mmol) with 2-(2-methoxyethoxy)-3-methoxybenzaldehyde (218 mg, 0.970 mmol) in presence of sodium ethoxide (94 mg, 1.380 mmol) in ethanol (15 ml) according to the procedure outlined in Example 24 to give 178 mg of the desired product as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 3.37 (s, 3H), 3.50 (br s, 2H), 3.78 (s, 3H), 4.04 (br s, 2H), 6.82 (d, J=15.6 Hz, 1H), 6.94-6.95 (m, 1H), 7.00-7.02 (m, 2H), 7.55-7.57 (m, 2H), 7.62-7.64 (m, 2H), 7.84-7.86 (m, 2H), 8.05-8.07 (m, 1H), 8.27 (d, J=15.6 Hz, 1H), 8.85-8.87 (m, 1H); ESI-MS (m/z) 553.81 (M+H)+.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.N1CCCCC1.[S:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29]([OH:33])([C:31]#[CH:32])[CH3:30]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:32]#[C:31][C:29]([C:25]4[S:24][CH:28]=[CH:27][N:26]=4)([OH:33])[CH3:30])[CH:10]=3)[CH:6]=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: Nc1nccc(-n2ncc3ccc(I)cc32)n1
Reactant: C#CC(C)(O)c1nccs1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC(O)(C#Cc1ccc2cnn(-c3ccnc(N)n3)c2c1)c1nccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-(6-iodo-1H-indazol-1-yl)pyrimidin-2-amine (1-a1) (150 mg, 0.285 mmol) and piperidine (1 mL) was added tetrakis(triphenylphosphine)palladium (49.3 mg, 0.043 mmol), copper(I) iodide (8.1 mg, 0.043 mmol) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (I-1) (131 mg, 0.854 mmol). The reaction was purged with N2 and stirred at RT for 30 min. The reaction mixture was concentrated in vacuo and the residue purified by reverse phase preparative HPLC to afford the title compound: 1H NMR (500 MHz, DMSO) δ 1.95 (3H, s), 7.04 (2H, br. s.), 7.08-7.13 (2H, m), 7.35 (1H, dd, J=8.20, 1.26 Hz), 7.70 (1H, d, J=3.15 Hz), 7.79 (1H, d, J=3.15 Hz), 7.89 (1H, d, J=8.51 Hz), 8.30 (1H, d, J=5.67 Hz), 8.50 (1H, s), 8.91 (1H, s). LC-MS: m/z=+363.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:29]([CH2:30][CH3:31])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([C@@H:18]4[CH2:20][C@H:19]4[NH:21]C(=O)OC(C)(C)C)=[CH:14][CH:13]=3)[N:9]=[CH:10][C:5]=2[C:4](=[O:32])[C:3]=1[C:33](=[O:35])[NH2:34].[ClH:36]>ClCCl.CO.O1CCOCC1.CCOCC>[ClH:36].[NH2:1][C:2]1[N:29]([CH2:30][CH3:31])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([C@@H:18]4[CH2:20][C@H:19]4[NH2:21])=[CH:16][CH:17]=3)[N:9]=[CH:10][C:5]=2[C:4](=[O:32])[C:3]=1[C:33]([NH2:34])=[O:35]
Reactant: CCn1c(N)c(C(N)=O)c(=O)c2cnc(Nc3ccc([C@@H]4C[C@H]4NC(=O)OC(C)(C)C)cc3)nc21
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CCn1c(N)c(C(N)=O)c(=O)c2cnc(Nc3ccc([C@@H]4C[C@H]4N)cc3)nc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 120.2 %

Procedure:
To a suspension of 0.46 g (0.96 mmol) of the product prepared in step 15.4 in 20 mL of a dichloromethane/methanol mixture (1/1) are added 4.8 mL (19.2 mmol) of 4N hydrogen chloride in dioxane. The mixture is stirred for 5 hours at room temperature and then diluted with ether, and the solid is drained by suction, rinsed with ether and dried in an oven under vacuum. 0.48 g of a dark violet solid is obtained, and is used as obtained in the following step. Yield (dihydrochloride)=quantitative.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][CH:6]([CH2:10][C:11](=[O:29])[N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH2:14][CH2:13]1)[C:7]([OH:9])=O.[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:37][CH2:36]1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][CH:6]([CH2:10][C:11]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH2:16][CH2:17]1)=[O:29])[C:7]([N:44]1[CH2:45][CH2:46][CH:41]([CH:38]2[CH2:37][CH2:36][N:35]([CH3:34])[CH2:40][CH2:39]2)[CH2:42][CH2:43]1)=[O:9]
Reactant: CN1CCC(C2CCNCC2)CC1
Reactant: Cc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1C
Product: Cc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(C)CC3)CC2)cc1C

Procedure:
Prepared analogously to Example 76e) from 2-(3,4-dimethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 1-methyl-[4,4′]bipiperidinyl
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13]([O:15]C(OCC)=O)=O)[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[S:3]1[CH:4]=[CH:5][S:1][C:2]1=[C:6]([C:13](=[O:15])[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7]([O:9][CH:10]([CH3:11])[CH3:12])=[O:8]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)OC(=O)C(C(=O)OC(C)C)=C1SC=CS1
Solvent: ClCCl
Product: CC(C)OC(=O)C(C(=O)Nc1ccccc1)=C1SC=CS1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Isopropyl 2-(1,3-dithiol-2-ylidene)-2-(ethoxycarbonyloxy-carbonyl)acetate (12.72 g) and aniline (3.73 g) were dissolved in methylene chloride (100 ml). The mixture was stirred at room temperature for 24 hrs. The reaction mixture was washed with aqueous sodium hydroxide solution, dil-HCl and then water. The methylene chloride layer was dried and the solvent was distilled. The resultant residue was recrystallized from ethyl acetate to obtain the pure product. (11.3 g, 88.0%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:17][C:18]1([CH3:28])[CH2:27][N:21]2S(=O)(=O)O[CH2:24][C@H:20]2[CH2:19]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH2:24][C@H:20]1[CH2:19][C:18]([CH3:28])([CH3:17])[CH2:27][NH:21]1
Reactant: CC1(C)C[C@@H]2COS(=O)(=O)N2C1
Reactant: Clc1cncc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CN[C@@H](Cc2c(Cl)cncc2Cl)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a solution of 3,5-dichloropyridine (796 mg, 5.38 mmol) in THF (9.0 mL) at −78° C. was added lithium diisopropylamide (2.0 M heptane/THF/ethylbenzene, 3.41 mL, 6.82 mmol) dropwise. After stirring for 1 h at this temperature, a solution of (R)-5,5-dimethyltetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (686 mg, 3.59 mmol) in THF (9.0 mL) was added dropwise at −78° C. and the mixture was allowed to warm to room temperature over 3 h and then stirred at room temperature for 4 h. After evaporation of the solvent, the resulting beige foam was treated with hot (80° C.) 2 N HCl (8 mL) and EtOH (8 mL) overnight. The reaction mixture was concentrated under reduced pressure (rotary evaporator) and the mixture was treated with ice and basified with 5 N NaOH (8 mL) and extracted with EtOAc (2×75 mL). The organic extracts were dried, evaporated and purified by chromatography on an ISCO Combiflash™ RF (25 g Thomson SingleStep column, using a gradient of 0-10% MeOH in DCM) affording (R)-3,5-dichloro-4-((4,4-dimethylpyrrolidin-2-yl)methyl)pyridine (748 mg, 2.89 mmol, 80% yield) as an orange oil. MS (ESI) 259.1, 261.0 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]2[C:8]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][CH2:12][C:6]2=[N:5][N:4]=1.[C-:24]#[N:25].[K+]>CS(C)=O>[Cl:23][C:20]1[CH:21]=[CH:22][C:8]2[N:7]3[C:3]([CH2:2][C:24]#[N:25])=[N:4][N:5]=[C:6]3[CH2:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]=2[CH:19]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CBr)n1-2
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: N#CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
In the same manner 1-bromomethyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine can be condensed with potassium cyanide in dimethylsulfoxide to give 8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-acetonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:8][C:7]=1[CH3:19])=[O:5])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:8][C:7]=1[CH2:19][Br:20])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1sc(-c2cccc(OC)c2)nc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(-c2cccc(OC)c2)nc1CBr
Temperature: 25 °C
Yield: 94.4 %

Procedure:
A mixture of 2-(3-methoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester (3.01 g, 10.88 mmole), N-bromosuccinimide (2.03 g, 11.42 mole) and benzoyl peroxide (132 mg, 0.54 mmole) in carbon tetrachloride (40 ml) was refluxed for 16 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (3.66 g). MS: (+) m/z 355.92, 357.92 (M+1, 79Br/81Br).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][CH2:24][CH3:25])[N:14]([CH2:15][CH2:16][CH2:17][O:18][N:19]=[C:20]([CH3:22])[CH3:21])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)CC>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][CH2:24][CH3:25])[N:14]([CH2:15][CH2:16][CH2:17][O:18][N:19]=[C:20]([CH3:22])[CH3:21])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCON=C(C)C
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CCCON=C(C)C
Temperature: 100 °C
Yield: 55.8 %

Procedure:
In a pressure vessel under a nitrogen atmosphere, acetone O-[3-(4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]oxime (500 mg, 1.20 mmol), phenylboronic acid (219 mg, 1.80 mmol), a solution of palladium (II) acetate (2.7 mg, 0.012 mmol) in hot toluene (0.5 mL), triphenylphosphine (9.5 mg, 0.036 mmol), and 2 M aqueous sodium carbonate (0.72 mL, 1.44 mmol) were combined in 5:1 n-propanol:water (2.4 mL). The solution was placed under vacuum and back-filled with nitrogen three times. The pressure vessel was sealed and heated at 100° C. overnight, then was allowed to cool to ambient temperature. Chloroform (60 mL) was added and the mixture was washed with water (2×10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 0-35% CMA in chloroform) to yield a solid that was triturated twice with acetonitrile and isolated to yield 278 mg of acetone O-[3-(4-amino-7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]oxime as a white powder, mp 164.0-165.0° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[NH:22]1[CH:26]=[N:25][C:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[N:23]1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:24]2[N:25]=[CH:26][N:22]([C:2]3[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=4)[N:3]=3)[N:23]=2)[CH:28]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Reactant: c1cncc(-c2nc[nH]n2)c1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4cccnc4)n3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidine (example A.2) (0.16 g, 0.5 mmol) and 3-(1H-[1,2,4]-triazol-3-yl)-pyridine [CAS-No. 23195-63-3] (0.075 g, 0.51 mmol) according to the general procedure IVa. Obtained as a light brown solid (0.095 g, 44%). MS (ISP) 437.3 [(M+H)+]; mp 190° C.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[O:5]1[C:7]([CH3:24])([CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:6]1>C(O)C>[OH:2][CH2:1][CH2:3][NH:4][CH2:24][C:7]([CH3:6])([OH:5])[CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCOCC1(C)CO1
Reactant: NCCO
Solvent: CCO
Product: CCCCCCCCCCCCCCOCC(C)(O)CNCCO
Temperature: 80 °C
Yield: 67.9 %

Procedure:
A 100-ml flask equipped with a stirrer and dropping funnel was then charged with 16.8 g (280 mmol) of ethanolamine and 15 g of ethanol. While stirring the mixture at 80° C., an ethanol solution of 5.00 g (17.6 mmol) of 1,2-epoxy-2-methyl-3-tetradecyloxypropane was added dropwise over 3 hours. The contents were stirred further for 2 hours. The resultant reaction mixture was concentrated under reduced pressure, and the resultant residue was purified by column chromatography on silica gel, thereby obtaining 4.13 g (yield: 68%) of the title compound.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:15]1([CH2:21][CH2:22][NH:23][C:24](=O)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[C:25]1([C:24]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:21][CH2:22][N:23]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(NCCc1ccccc1)c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: c1ccc(C2=NCCc3ccccc32)cc1
Yield: 97.1 %

Procedure:
75.5 g (532 mmol, 1.2 eq.) of P2O5 are added with stirring to a solution of 100.0 g (446 mmol) of N-(2-phenylethyl)benzamide in 375 ml of xylene. 124.1 ml (1.34 mol, 3.0 eq.) of PPCl3 are subsequently added, and the reaction mixture is refluxed with TLC monitoring. When the conversion is complete, the reaction solution is poured while hot onto ice and carefully adjusted to pH=12 using 20% NaOH. The phosphate which precipitates in the process is dissolved by addition of water. The product is subsequently extracted with toluene, converted into the hydrochloride using 1 N HCl and extracted with sufficient water. The aqueous phase is rendered basic again using 20% NaOH with ice-cooling, the reaction product is extracted with toluene, dried over MgSO4 and evaporated to dryness under reduced pressure, giving 89.7 g (432.9 mmol) of a viscous yellow oil, corresponding to 97% of theory.