Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][C@H:23]([CH2:25][N:26]=[N+]=[N-])[O:22][C:21]4=[O:29])=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:24][C@H:23]([CH2:25][NH2:26])[O:22][C:21]4=[O:29])=[CH:18][CH:19]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(N3C[C@H](CN)OC3=O)cc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.8 %

Procedure:
A mixture of 1-[4-{5(R)-azidomethyl-2-oxo-oxazolidin-3-yl}-phenyl]-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Intermediate IV, Step 6) (750 mg, 1.95 mmol) and triphenylphosphine (700 mg, 2.1 mmol) in THF (30 mL) was stirred at r.t. for 6 h. Water (1.5 mL) was added and the reaction mixture was stirred at 80° C. for 12 h. The reaction mixture was then diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.5:9.5 MeOH:CHCl3) to provide the title compound (450 mg, 62%) as off white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH2:14][OH:15])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl:16]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH2:14][OH:15])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:16])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(N)c1NCCO
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)c(N)c1NCCO
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
To a solution of methyl 3-amino-2-[(2-hydroxyethyl)amino]benzoate (114.1 mg, 0.543 mmol) in dichloromethane (2.7 mL) was added N-chlorosuccinimide (14.5 mg, 1.09 mmol) at room temperature. The mixture was stirred at room temperature for 1.5 hr and at 30° C. for 0.5 hr. Aqueous sodium sulfite was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-70% ethyl acetate/n-hexane gradient mixture to give the title compound (29.0 mg, 0.12 mmol, 22%) as an orange amorphous.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:15]1([C:13]2[N:10]=[C:6]3[CH:7]=[CH:8][C:9]4[O:1][CH2:2][CH2:3][C:4]=4[N:5]3[CH:12]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc2c(n1)CCO2
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(-c2cn3c4c(ccc3n2)OCC4)cc1
Temperature: 80 °C
Reaction time: 14 h
Yield: 15.7 %

Procedure:
To a solution of 2,3-dihydrofuro[3,2-b]pyridin-5-amine (500 mg, 3.67 mmol) in ethanol (30 mL) were added 2-bromo-1-phenylethanone (730 mg, 3.67 mmol) and sodium carbonate (467 mg, 4.40 mmol), and the mixture was stirred at 80° C. for 14 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→50/50) to give the title compound (136 mg, yield 16%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][O:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17]C)=[O:16])[N:4]=1.[OH-].[K+]>C(O)C.O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([CH2:11][O:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([OH:17])=[O:16])[N:6]=1
Reactant: COC(=O)c1ccccc1OCc1nc(OC)cc(OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)nc(COc2ccccc2C(=O)O)n1
Yield: 90.9 %

Procedure:
1.5 g of methyl 2-[(4,6-dimethoxy-2-pyrimidyl)methyloxy]benzoate was dissolved in 10 ml of ethanol. 10 ml of water and then 7 ml of 1N aqueous potassium hydroxide solution were added to this solution, and the mixture was stirred until it got to be clear (about 4 hours). The reaction solution was diluted with water and washed with ether, the water layer was neutralized with 1N hydrochloric acid and extracted with chloroform, the extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 1.3 g of 2-[(4,6-dimethoxy-2-pyrimidyl)methyloxy]benzoic acid (yield 91%).
Reaction SMILES: C([N:5]1[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([O:14][CH3:15])[C:8]=2[C:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[N:6]1)(C)(C)C>FC(F)(F)C(O)=O.O>[CH3:15][O:14][C:9]1[C:8]2[C:7]([C:16]3[CH:17]=[CH:18][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:20][CH:21]=3)=[N:6][NH:5][C:13]=2[CH:12]=[CH:11][N:10]=1
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1nccc2[nH]nc(-c3ccc(S(N)(=O)=O)cc3)c12
Temperature: 25 °C
Yield: 75.7 %

Procedure:
4-(1-tert-Butyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (878 mg) obtained in Step D of Example 86 was dissolved in a mixed solvent of trifluoroacetic acid (50 mL)/water (5 mL), and the solution was heated with reflux for 24 hr. The reaction mixture was allowed to be cooled to room temperature, and concentrated under reduced pressure. The residue was extracted with ethyl acetate and saturated aqueous sodium hydrogencarbonate solution, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (561 mg).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].BrBr.[NH2:13][C:14]([NH2:16])=[S:15]>C(O)(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:13]=[C:14]([NH2:16])[S:15][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: NC(N)=S
Agent: BrBr
Solvent: CC(=O)O
Product: CC(=O)N1CCc2nc(N)sc2C1
Reaction time: 4 h
Yield: 10.2 %

Procedure:
N-Acetyl4-piperidone (7.05 g, 0.05 mol) in acetic acid (35 mL) was treated dropwise with bromine (8.0 g, 0.05 mol) in acetic acid (10 mL) at room temperature. After 4 h, the formed precipitate was collected on a filter, washed with diethyl ether and air-dried. This crude intermediate (3.01 g) was dissolved in ethanol (20 mL) and after the addition of thiourea (0.76 g, 10.0 mmol)the reaction mixture was refixed for 4 h. The solvent was removed in vacuo. Water (20 mL) was added and the pH was adjusted to 9. Extraction with DCM, drying (sodium sulfate) and removal of the organic phase gave 1.1 g of a crude product. Modification by flash chromatography on silica gel gave 202 mg (10%) of 5-acetyl4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-ylamine. This compound was sulfonylated with 3-chloro-2-methylbenzene sulfonyl chloride (234 mg, 1.02 mmol) in pyridine according to METHOD A. After workup, the final product was crystallised from methanol to afford 75 mg (%) of white crystals: 1H NMR (DMSO-d6, 70° C.) δ 2.05 (s, 3H), 2.66 (s, 3H), 3.09 (m, 2H), 3.69 (m, 2H), 4.38 (m 2H), 7.37 (t, 1H), 7.64 (d, 1H), 7.91 (d, 1H), 12.53 (br s, NH).
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[NH2:31][C:32]1[CH:33]=C(C=[CH:38][CH:39]=1)CN>>[NH2:31][C:32]1[CH:33]=[C:11]([CH:12]=[CH:38][CH:39]=1)[CH2:10][NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: NCc1cccc(N)c1
Product: Nc1cccc(CNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)c1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 3-aminobenzylamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 364 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (1H, br. s.) 10.41 (1H, s) 8.58 (1H, t, J=5.93 Hz) 8.03 (1H, d, J=5.47 Hz) 7.80 (1H, d, J=5.42 Hz) 7.50 (1H, d, J=5.42 Hz) 7.31 (1H, dd, J=3.44, 2.32 Hz) 6.93 (1H, t, J=7.69 Hz) 6.85 (1H, d, J=5.47 Hz) 6.50 (1H, s) 6.35-6.46 (3H, m) 5.08 (2H, br. s.) 4.32 (2H, d, J=5.91 Hz)
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][NH:5][CH2:4][C@@H:3]1[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[F:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26](=[O:33])[N:27]2[CH2:30][CH:31]=O)=[N:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[F:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26](=[O:33])[N:27]2[CH2:30][CH2:31][N:5]2[CH2:6][C@@H:2]([OH:1])[C@@H:3]([CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:4]2)=[N:22][CH:21]=1
Reactant: O=CCn1c(=O)ccc2ncc(F)cc21
Reactant: O=C(NC[C@H]1CNC[C@H]1O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(NC[C@H]1CN(CCn2c(=O)ccc3ncc(F)cc32)C[C@H]1O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Phenylmethyl {[(3R,4S)-4-hydroxy-3-pyrrolidinyl]methyl}carbamate (1.17 g; 4.560 mmol) and (7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde (as the methyl hemiacetal)) (855 mg, 4.17 mmol) were combined in anhydrous DCM (5 ml) and anhydrous MeOH (1 ml) with a spatula of solid sodium carbonate. The reaction mixture was stirred under nitrogen for 1 h then sodium triacetoxyborohydride (2.76 g; 12.44 mmol) was added and stirred overnight. The reaction mixture was concentrated and the title compound was obtained as a pale yellow oil (1.69 mg, 87%) after column:chromatography (90:10: DCM:MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[CH2:10]([CH:17](C(C)=O)[C:18](OCC)=[O:19])C1C=CC=CC=1>OS(O)(=O)=O>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[OH:9])[O:6][C:18](=[O:19])[CH:17]=[CH:10]2
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Reactant: Oc1ccc(Cl)c(O)c1
Agent: O=S(=O)(O)O
Product: O=c1ccc2cc(Cl)c(O)cc2o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 104.9 %

Procedure:
4-Chlororesorcinol (26.25 g, 0.182 mol) and ethyl 2-benzylacetoacetate (40 g, 0.182 mol) are mixed in 70% H2SO4 (350 mL) at 0° C. The reaction mixture is stirred at room temperature for 72 hours and poured into ice water. The solid is filtered and washed with water. The crude product is recrystallized from ethanol/chloroform to afford 6-chloro-7-hydroxy coumarin intermediate (37.52 g, 68.7%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1.ClC1C=CC=C(C(OO)=[O:18])C=1.CCCCCCC>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1)=[O:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc(Br)cn1
Solvent: CCCCCCC
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ncc(Br)cn1
Yield: 90 %

Procedure:
The title compound was prepared by oxidation of 2-methylthio-5-bromopyrimidine by m-chloroperbenzoic acid in chloroform as described in Example 39; yield 90%, m.p. 90° C. (n-heptane). 1H NMR (CDCl3): δ2.91 (Me),. 8.90 (H-4, H-6).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH2:21])[C:19](=[O:22])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:3])[CH3:2].[Cl:23][CH:24]([Cl:39])[C:25]([O:27][N:28]=[C:29]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:30](Cl)=[O:31])=[O:26]>C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH:21][C:30](=[O:31])[C:29](=[N:28][O:27][C:25](=[O:26])[CH:24]([Cl:39])[Cl:23])[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:19](=[O:22])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(Cl)C(=NOC(=O)C(Cl)Cl)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)C(Cl)Cl)c3ccccc3)[C@H]2SC1
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of t-butyl 3-acetoxymethyl-7β-aminoceph-3-em-4-carboxylate (3.28 g) in ethyl acetate (25 ml.) was added a solution of 2-dichloroacetoxyimino-2-phenylacetyl chloride (syn-isomer) in ethyl acetate (25 ml.) dropwise with stirring. The solution became warm and a precipitate formed. After two hours, the solution was filtered, washed successively with 2 N-hydrochloric acid, water, and saturated sodium bicarbonate solution, dried, and evaporated to give a yellow foam which solidified on standing, and was triturated with petroleum spirit giving t-butyl 3-acetoxymethyl-7β-(2-dichloroacetoxyimino-2-phenylacetamido)-ceph-3-em-4-carboxylate (4.0 g; 70%), νmax. (CHBr3) 3420 (NH), 1796 (β-lactam), 1730 and 1230 (acetate), 1700 and 1512 cm-1 (CONH), τ (DMSO-d6) values include 2.1-2.5 (multiplet; aromatic protons), 2.98 (singlet; CHCl2), 7.6 (singlet; CH3CO), 8.5 (singlet; t-butyl ester).
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][NH:5][C:6](=[O:33])[CH2:7][CH:8]1[N:14]([C:15](=[O:22])[C:16]2C=CN=CC=2)[CH2:13][C:12]2[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=2[N:10]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:9]1=[O:32].C(OC(=O)C)(=O)C>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:15]([N:14]1[CH2:13][C:12]2[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=2[N:10]([CH2:27][C:28]([CH3:30])([CH3:31])[CH3:29])[C:9](=[O:32])[CH:8]1[CH2:7][C:6]([NH:5][CH2:4][C:3]1[CH:34]=[CH:35][CH:36]=[CH:37][C:2]=1[F:1])=[O:33])(=[O:22])[CH3:16]
Reactant: CC(C)(C)CN1C(=O)C(CC(=O)NCc2ccccc2F)N(C(=O)c2ccncc2)Cc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1Cc2ccccc2N(CC(C)(C)C)C(=O)C1CC(=O)NCc1ccccc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 83.9 %

Procedure:
To a solution of the compound (0.15 g) obtained in Example 1B (1) in pyridine (6 ml) were added acetic anhydride (0.20 g) and 4-dimethylaminopyridine (0.05 g), and the mixture was stirred at room temperature for 14 hrs. The solvent was evaporated, and the residue was purified by silica gel column chromatography and recrystallized from hexane-ethyl acetate to give the title compound (0.11 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[C:7]([C:8]2[C:9](=[O:29])[N:10]([CH:26]([CH3:28])[CH3:27])[C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:13]=2[CH3:14])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)#[N:31].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH:26]([N:10]1[C:9](=[O:29])[C:8]([C:7]2[C:2]([C:35]3[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[CH:33][CH:34]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[C:13]([CH3:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:11]1=[O:25])([CH3:28])[CH3:27]
Reactant: Cc1c(-c2cccnc2Br)c(=O)n(C(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(-c2cccnc2-c2ccc(C#N)cc2)c(=O)n(C(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
5-(2-Bromopyridin-3-yl)-3-isopropyl-6-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 189) (132 mg) and 4-cyanophenylboronic acid (166 mg) were dissolved in 1,4-dioxane (10 ml). Thereto were added under nitrogen atmosphere water (1 ml), sodium carbonate (239 mg) and tetrakis(triphenylphosphine)palladium (33 mg) and the resulting mixture was stirred with heating under reflux for one and a half hours. The reaction mixture was cooled to room temperature, and thereto was then water and the resulting mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with saturated saline (50 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: firstly hexane/ethyl acetate, secondly chloroform/methanol) to afford 4-(3-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)pyridin-2-yl)benzonitrile (118 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[CH:20]4)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: Nc1ccc2[nH]ccc2c1
Product: Brc1ccc2[nH]c3c(c2c1)CCCC3Nc1ccc2[nH]ccc2c1

Procedure:
6-Bromo-N-(1H-indol-5-yl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (100 mg, 0.76 mmol) and 5-aminoindole (100 mg, 0.76 mmol) in a similar manner as described above to give 54 mg (37%) of a white solid; 1H-NMR (DMSO-d6): δ 11.08 (s, 1H), 10.61 (s, 1H), 7.55 (d, 1H), 7.23 (d, 1H), 7.14-7.11 (m, 2H), 7.10 (d, 1H), 6.84-6.83 (m, 1H), 6.65 (dd, 1H), 6.18-6.17 (m, 1H), 5.21 (d, 1H), 4.77-4.71 (m, 1H), 2.68-2.54 (m, 2H), 2.02-1.89 (m, 2H), 1.84-1.73 (m, 2H); MS m/z (M+1) 378, 380.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CN(C)C1CCc2[nH]c3ccc(NS(=O)(=O)c4ccc(Cl)cc4)cc3c2C1
Yield: 61.9 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 14.1 mg (0.067 mMol) 4-chlorobenzenesulfonyl chloride, 11.5 mg (64%) of the title compound were recovered as a light beige solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>ClCCl>[C:1]([O:5][C:6]([NH:7][C:8]1[N:9]=[C:10]([CH2:14][O:15][C:33](=[O:35])[CH3:34])[CH:11]=[CH:12][CH:13]=1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)n1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1cccc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
(6-Hydroxymethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (0.85 g, 3.79 mmol) was dissolved in dichloromethane (30.00 ml) and triethylamine (1.32 ml) and treated with dimethylaminopyridine (0.09 g, 0.76 mmol) and acetic anhydride (0.43 g, 4.17 mmol). The mixture was stirred at room temperature for 10 min, then partitioned between water and dichloromethane. The organic layer was dried over sodium sulphate and evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate) to yield acetic acid 6-tert-butoxycarbonylamino-pyridin-2-ylmethyl ester (0.85 g, 84%) as a white solid, MS (ISP): m/e=267.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([N+:10]([O-])=O)[N:3]=1>C(OCC)(=O)C.[Ni]>[NH2:10][C:4]1[C:5]([NH:8][CH3:9])=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=1
Reactant: CNc1ccc(C)nc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CNc1ccc(C)nc1N

Procedure:
8.35 g (50 mMol) of 2-Methyl-5-methylamino-6-nitro-pyridine (Heterocycles 38, 529 (1994)) were dissolved in 300 l ethyl acetate and hydrogenated with 1.5 g Raney nickel for 3.5 hours at room temperature. Then the catalyst was filtered off and the filtrate was evaporated down. After crystallisation of the resulting residue from petroleum ether, 5.75 g (84% of theory) were obtained as olive-green crystals. C7H11N3 (137.20) Melting point: 112-113° C.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[C:6]([NH:8][C:9]1[C:10]([NH:16][CH3:17])=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=1)=O)[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)(C)(C)C>O>[CH2:1]([S:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[C:6]1[N:16]([CH3:17])[C:10]2=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]2[N:8]=1)[CH3:2]
Reactant: CCSc1ccccc1C(=O)Nc1cc(C)cnc1NC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCSc1ccccc1-c1nc2cc(C)cnc2n1C
Temperature: 82 °C
Yield: 20.5 %

Procedure:
A mixture of 2-ethylsulfanyl-N-(5-methyl-2-methylaminopyridin-3-yl)-benzamide (1.40 g), tripotassium phosphate (1.97 g), and tert-butanol (10 ml) was stirred under reflux at 82° C. for 2 hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.27 g of 2-(2-ethylsulfanylphenyl)-3,6-dimethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 39).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:23][C:24]1[N:29]2[CH:30]=[CH:31][N:32]=[C:28]2[CH:27]=[CH:26][CH:25]=1)[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:33][C:34]([Cl:39])([Cl:38])[C:35](Cl)=[O:36]>CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl>[Cl:33][C:34]([Cl:39])([Cl:38])[C:35]([C:30]1[N:29]2[C:24]([CH2:23][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:17])[F:18])=[CH:25][CH:26]=[CH:27][C:28]2=[N:32][CH:31]=1)=[O:36]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N(CCCCNC(=O)C(F)(F)C(F)(F)F)Cc1cccc2nccn12
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(CCCCNC(=O)C(F)(F)C(F)(F)F)Cc1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Temperature: 0 °C
Yield: 44 %

Procedure:
To a solution of 11.78 g (25.36 mmol) of 5-[N-tert-butoxycarbonyl-N-(4-pentafluoropropionamidobutan-1-yl)aminomethyl]imidazo[1,2-a]pyridine and 13.94 g (114.36 mmol) of 4-(N,N-dimethylamino)pyridine in 250 ml of chloroform was added 8.50 ml (76.09 mmol) of trichloroacetyl chloride. The mixture was heated for 16 hours under reflux. The reaction mixture was poured into ice-water, and extracted with 100 ml of chloroform. The organic layer was washed with 200 ml of a saturated aqueous saline solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) to afford 6.80 g of the desired compound (44.0%, a pale yellow liquid).
Reaction SMILES: [C:1]1([CH:7]([CH2:10][OH:11])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].S(=O)(=O)(O)O>C(#N)C>[C:12]([O:11][CH2:10][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[N:9])(=[O:14])[CH3:13]
Reactant: N#CC(CO)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: CC(=O)OCC(C#N)c1ccccc1
Reaction time: 0.42 h
Yield: 98 %

Procedure:
A sample of this 2-phenyl-3-hydroxypropanenitrile (127 mg, 0.863 mmol) and acetic anhydride (106 μL, 1.1 mmol) in acetonitrile (250 μL) was treated with sulfuric acid (˜0.5 μL). After 25 min at ambient temperature, work-up as described above in Example 5 gave 160 mg (98%) product as a colorless oil.