Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10](OC(=O)C)(=[O:12])[CH3:11]>O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:10](=[O:12])[CH3:11])[CH:5]=[CH:4][C:3]=1[OH:9]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(O)c(Cl)c1
Temperature: 25 °C

Procedure:
The mixture was heated at reflux for 6 hours, cooled to ambient temperature and filtered. The filtrate was evaporated, and the residue treated with ether to give crude 2-chloro-4-aminophenol (10 g). The crude 2-chloro-4-aminophenol (3.5 g) was added to a mixture of water (50 ml) and acetic anhydride (5.7 ml). The reaction mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to ambient temperature and the supernatant was decanted away from an oil which gave a solid on standing. The solid was purified by flash column chromatography on silica gel (Merck Art. No 9385) using a 1:2(v/v) mixture of ethyl acetate and pentane as eluent to give 2-chloro-4-acetamidophenol as an oil (1.7 g); NMR: ([CD3 ]2SO): 2.0(3H,s), 6.85(1H,d), 7.2(1H,m), 7.68(1H,m) and 9.8(2H,m).
Reaction SMILES: [OH-].[Na+].[NH2:3][C@H:4]([C:8]([OH:10])=[O:9])[CH2:5][CH2:6][CH3:7].Br[CH2:12][CH3:13].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>O>[CH2:8]([N:3]([CH2:19][CH2:20][CH2:12][CH3:13])[C@H:4]([C:8]([OH:10])=[O:9])[CH2:5][CH2:6][CH3:7])[CH2:4][CH2:5][CH3:6]
Reactant: CCBr
Reactant: CCO
Reactant: CCC[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCN(CCCC)[C@@H](CCC)C(=O)O
Temperature: 70 °C
Reaction time: 5 h

Procedure:
In a mixture of 100 ml of ethanol and 40 ml of water were dissolved 8.0 g (200 mmol) of sodium hydroxide and 11.72 g (100 mmol) of L-norvaline. To the solution was added 27.41 g of 1-bromoethane, and the mixture was heated up to 70° C., followed by vigorously stirring for 5 hours. Thereafter, 4.0 g of sodium hydroxide was added thereto, and the stirring was continued for an additional time of 5 hours under the same condition. After the reaction, the reaction mixture was cooled, adjusted to a pH of 7 with sulfuric acid, and diluted with 1.5 liter of water to obtain N,N-di-n-butyl-L-norvaline as a fatty and oily product.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[BrH:16].C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[Br:16][CH2:3][CH2:2][CH2:1][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1)=[O:5]
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)C1CC1
Reactant: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C(CCCBr)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
20 g (88.6 mmol) of 4-chloro-3-nitrophenyl cyclopropyl ketone is added to a solution of 65 m of 32% HBr/acetic acid in 300 ml acetic acid and heated to 80° C. for 5 hr. The reaction mixture is cooled to room temperature and poured nto 1 L of 10% potassium carbonate solution, dried over MgSO4 filtered and treated with charcoal. The solvent is removed in vacuo, and the residue is crystallized from ether to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[C:12]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([N:27]=[C:28]=[S:29])(=[O:26])=[O:25])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[C:18]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([NH:27][C:28]([NH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1)=[S:29])(=[O:25])=[O:26]
Reactant: O=S(=O)(N=C=S)c1ccccc1-c1ccccc1
Reactant: COc1nc(N)nc(OC)n1
Solvent: Cc1ccccc1
Product: COc1nc(NC(=S)NS(=O)(=O)c2ccccc2-c2ccccc2)nc(OC)n1
Yield: 81.2 %

Procedure:
15.6 g of 2-amino-4,6-dimethoxy-1,3,5-triazine were suspended in 300 ml of dry toluene, and 27.5 g of 2-phenylbenzenesulfonyl isothiocyanate were added. The mixture was heated under reflux for 8 hours. After cooling, the resulting precipitate was collected by filtration and recrystallized from ethanol to give 35 g of 1-(2-biphenylylsulfonyl) 3-(4,6-dimethoxy-1,3,5-triazin-2-yl)thiourea represented by the following formula: ##STR28##
Reaction SMILES: C([C:3]1([CH2:13][O:14][C:15]2[C:23]([CH:24]3[CH2:26][CH2:25]3)=[CH:22][C:18]([C:19](O)=[O:20])=[C:17]([F:27])[CH:16]=2)[CH:10]2CC3[CH2:7][CH:8]([CH2:12][CH:4]1C3)[CH2:9]2)#N.C12CC1CCC(COC1C(C3CC3)=CC(C(O)=O)=C(F)C=1)C2.CS(N)(=O)=O.[N:55]1([S:59]([NH2:62])(=[O:61])=[O:60])[CH2:58][CH2:57][CH2:56]1>>[N:55]1([S:59]([NH:62][C:19](=[O:20])[C:18]2[CH:22]=[C:23]([CH:24]3[CH2:25][CH2:26]3)[C:15]([O:14][CH2:13][CH:3]3[CH2:10][CH2:9][CH:8]4[CH:12]([CH2:7]4)[CH2:4]3)=[CH:16][C:17]=2[F:27])(=[O:61])=[O:60])[CH2:58][CH2:57][CH2:56]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2CCC3CC3C2)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2CCC3CC3C2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(bicyclo[4.1.0]heptan-3-ylmethoxy)-5-cyclopropyl-2- fluorobenzoic acid and making variations as required to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as solid (0.026 g, 5%): 1H NMR (300 MHz, CDCl3) δ 8.66 (d, J=16.5 Hz, 1H), 7.60 (d, J=9.1 Hz, 1H), 6.59 (d, J=14.5 Hz, 1H), 5.78-5.54 (m, 2H), 4.25 (t, J=7.7 Hz, 4H), 3.96-3.85 (m, 2H), 2.35-2.17 (m, 4H), 2.11-1.64 (m, 5H), 1.28-1.23 (m, 1H), 1.06-1.00 (m, 2H), 0.96-0.91 (m, 2H), 0.70-0.66 (m, 2H); MS (ES+) m/z 423.1 (M+1).
Reaction SMILES: [CH2:1]([C@@H:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[CH3:44][C:32]1[N:31]([CH2:30][C:27]2[CH:28]=[CH:29][C:24]([C:19]3[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:25][CH:26]=2)[C:39]2[C:34]([C:33]=1[CH3:43])=[CH:35][C:36]([C:40](=[O:41])[NH:10][C@@H:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:1][CH3:2])=[CH:37][CH:38]=2
Reactant: CC[C@@H](N)c1ccccc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: CC[C@@H](NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C(=O)O)cc1)c1ccccc1

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using (R)-α-ethylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: O.NN.O=C1C2C(=CC=CC=2)C(=O)[N:6]1[CH2:15][C:16]([P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])([F:18])[F:17]>C(Cl)Cl>[NH2:6][CH2:15][C:16]([P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])([F:17])[F:18]
Reactant: CCOP(=O)(OCC)C(F)(F)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(F)(F)CN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrazine monohydrate was added to a methylene chloride solution of diethyl [2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1,1-difluoroethyl]phosphonate, for stirring at ambient temperature for one hour, to obtain diethyl (2-amino-1,1-difluoroethyl)phosphonate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:16]1([N:22]=[C:23]=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:22]([CH3:23])[CH3:16])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 16 h

Procedure:
To 1-(tert-butoxycarbonyl)-L-proline (5.0 g) in DCM (50 ml) at 5° C. was added dicyclohexylcarbodiimide (5.22 g) and N-hydroxysuccinimide (2.91 g). The mixture was stirred at this temperature for 16 h. The solid was filtered and the filtrate cooled to 5° C. To this mixture was added triethylamine (9.80 ml) and dimethylamine hydrochloride (2.80 g). The mixture was stirred at room temperature for 2 days. H2O (50 ml) was added and the phases were separated and the organics were washed with saturated sodium carbonate (2×20 ml) and brine (20 ml). This was then dried (MgSO4) and evaporated to dryness to afford the title compound as a white solid. Yield: 6.0 g.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[NH2:23])[C@H:11]([OH:25])[C@@H:10]1[OH:26].C(N(C(C)C)CC)(C)C.[S:36](Cl)([CH3:39])(=[O:38])=[O:37]>C1COCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:23][C:19]1[N:18]=[C:17]([Cl:24])[N:16]=[C:15]2[C:20]=1[N:21]=[CH:22][N:14]2[C@@H:12]1[CH2:13][C@H:9]([NH:8][S:36]([CH3:39])(=[O:38])=[O:37])[C@@H:10]([OH:26])[C@H:11]1[OH:25]
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1C[C@H](N)[C@@H](O)[C@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N[C@H]1C[C@@H](n2cnc3c(N)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(1S,2R,3S,5R)-3-Amino-5-(6-amino-2-chloro-purin-9-yl)-cyclopentane-1,2-diol trifluoroacetate (20 mg, 39 μmol) and diisopropylethylamine (25 mg, 190 μmol) are placed in a flask with dry THF (1 ml). Mesyl chloride (4.5 mg, 39 μmol) is added and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 3 hours. The solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.1% TFA). MS (ES+) m/e 363 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][S:5][CH3:6].[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][C:30](=[O:32])[C:29]5([CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[N:28]=4)=[CH:23][CH:22]=3)[N:20]=2)[CH2:12][CH2:11]1>CN(C)C=O>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH:28][C:29]4([C:30]([NH:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:32])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]4)=[O:31])=[CH:25][CH:26]=3)[N:20]=2)[CH2:12][CH2:11]1
Reactant: CSCC[C@H](N)CO
Reactant: CN1CCN(c2nc(-c3ccc(C4=NC5(CCCCC5)C(=O)O4)cc3)cs2)CC1
Solvent: CN(C)C=O
Product: CSCC[C@@H](CO)NC(=O)C1(NC(=O)c2ccc(-c3csc(N4CCN(C)CC4)n3)cc2)CCCCC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
100 mg (0.74 mmol) of L-methioninol was added to a solution of 250 mg (0.68 mmol) of 2-[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in 20 ml of dimethylformamide. After the mixture was stirred at 80° C. for 15 hours, the reaction solution was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was successively washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, and diisopropyl ether was added to the residue to wash the crystal to obtain 319 mg (86%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])/[C:10](/[C:20]2[CH:25]=[CH:24][C:23]([O:26]COC)=[CH:22][CH:21]=2)=[C:11](/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)\[CH2:12][CH3:13])=[CH:4][CH:3]=1.Cl.O>CO.O1CCOCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])/[C:10](/[C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)=[C:11](/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)\[CH2:12][CH3:13])=[CH:6][CH:7]=1
Reactant: CC/C(=C(\C(=O)Nc1ccc(O)cc1)c1ccc(OCOC)cc1)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CC/C(=C(\C(=O)Nc1ccc(O)cc1)c1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of 6a (45 mg, 0.112 mmol) in MeOH (1 ml) was added a solution of 4N HCl in dioxane (0.3 ml) under ice cooling, and the mixture was stirred at room temperature for 2 h. H2O was poured into the reaction mixture under ice cooling, and the whole was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, and then concentrated. The residue was crystallized with Et2O to give 7a (76%). 7a: colorless powder; 1H-NMR (CD3OD) δ 0.97 (3H, t, J=7.5 Hz), 2.64 (2H, q, J=7.5 Hz), 6.51 (2H, d, J=8.8 Hz), 6.76 (2H, d, J=8.8 Hz), 6.92 (2H, d, J=8.8 Hz), 7.12-7.25 (5H, m), 7.40 (2H, d, J=8.8 Hz). HRMS calcd for C23H22NO3: 360.1600. Found: 360.1605.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C([Mg]Cl)C=C.C(OCC)C.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:30][C:31](=[O:39])[C:32]3[CH:38]=[N:37][CH:36]=[CH:35][C:33]=3[N:34]=2)=[C:25]([O:40][CH:41]2[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]2)[CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>C1COCC1.C(OCC)(=O)C>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([NH:34][C:33]2[CH:35]=[CH:36][N:37]=[CH:38][C:32]=2[C:31]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=2)=[O:39])=[O:30])=[C:25]([O:40][CH:41]2[CH2:42][CH2:43][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:45][CH2:46]2)[CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2-c2nc3ccncc3c(=O)o2)CC1
Agent: C=CC[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Nc2ccncc2C(=O)Nc2ccc(Cl)cn2)CC1
Yield: 72.4 %

Procedure:
To a stirring solution of 2-amino-5-chloropyridine (0.055 g, 0.42 mmol) in THF (5 mL) at 0° C., was added a 1.0 M solution of allylmagnesium chloride in diethyl ether (0.4 mL, 0.4 mmol). To this solution was then added a solution of 2-[4-tert-butyl-2-(1-Boc-piperidin-4-yloxy)-phenyl]-4H-pyrido[4,3-d][1,3]oxazin-4-one (0.12 g, 0.25 mmol) in THF (3 mL). After several hours, the solution was diluted with ethyl acetate and washed twice with brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo to give a white solid which was washed with diethyl ether and dried in vacuo to give the title compound (0.11 g, 70%).
Reaction SMILES: [C:1]([CH:4]([CH2:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>C(O)C>[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([N:26]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:1]2[CH3:2])=[CH:24][CH:23]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(CC(=O)c1ccc(Cl)cc1Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1C
Yield: 97 %

Procedure:
10 g of the compound obtained in step A) are dissolved in 45 ml of anhydrous ethanol in the presence of 4.1 g of 4-chloroaniline. The mixture is heated at the reflux point of the ethanol for 3 days. After evaporating off the solvent, the expected product is crystallized from an isopropanol/ethanol mixture. 12.5 g of white crystals are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH2:22](I)[CH2:23][CH3:24]>>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]=[C:7]2[N:12]([CH2:22][CH2:23][CH3:24])[C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[N:17][C:9]=3[S:8]2)=[CH:4][CH:3]=1
Reactant: CCCI
Reactant: O=c1nc(Nc2ccc(Br)cc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Product: CCCn1c(=Nc2ccc(Br)cc2)sc2ncccc2c1=O
Yield: 80.1 %

Procedure:
The reaction procedure of Example 11 was followed except that 900 mg (2.69 mmol) of 2-(4-bromoanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 24 mg of lithium hydride and 503 mg of propyl iodide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 811 mg of 2-[(4-bromophenyl)imino]-2,3-dihydro-3-propyl-4H-pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from a mixture of ether and hexane) as a low polarity substance and 103 mg of 2-[N-(4-bromophenyl)-N-propylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from ether) as a high polarity substance.
Reaction SMILES: Cl.Cl.[C:3]1([N:9]2[CH2:15][CH2:14][NH:13][NH:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24].C(N(CC)C(C)C)(C)C>CN(C)C=O>[N+:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:13]1[CH2:14][CH2:15][N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:10][CH2:11][NH:12]1)([O-:25])=[O:24]
Reactant: c1ccc(N2CCNNCC2)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1N1CCN(c2ccccc2)CCN1

Procedure:
A mixture of hexahydro-5-phenyl-1H-1,2,5-triazepine dihydrochloride (15.0 g), 1-fluoro-2-nitrobenzene (9.84 ml), N,N-diisopropylethylamine (36.5 ml) in N,N-dimethylformamide (150 ml) was magnetically stirred and heated at 75°-80° for 5 hours under nitrogen. The solution was evaporated under oil pump vacuum and the residual syrup was mixed with chloroform and dilute sodium hydroxide. The aqueous phase was extracted once more with chloroform and the combined chloroform extracts were dried (MgSO4). The solution was evaporated to a syrup which was subjected to an oil pump vacuum. This material in benzene was applied to a column (80×4.0 cm) of dry column grade neutral alumina (Woelm) prepacked in benzene. Elution was with benzene and monitoring of fractions was by t.l.c. on Alox 25 uv254 plates (Brinkmann) with benzene as developer. The fractions containing the major component were evaporated to a syrup which was crystallized from benzeneheptane; wt. 13.82 g (78%), mp=118°-120°. Recrystallization from benzeneheptane gave pure titled product, mp=119° -121°.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH2:1]([NH:8][C:9]1[C:10]([NH2:16])=[CH:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Br)cc1NCc1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of N-benzyl-5-bromo-2-nitroaniline (700 mg, 2.28 mmol) in EtOH (8 mL) and water (8 mL) was added iron powder (766 mg, 13.7 mmol) and NH4Cl (733 mg, 13.7 mmol). The mixture was stirred at 60° C. for 4 h. The reaction solution was filtered with the filtrate concentrated to remove EtOH. The residue was diluted with water and extracted with EtOAc with the organic layer concentrated to give the crude N1-benzyl-5-bromobenzene-1,2-diamine. The crude product was used in next step without further purification. LCMS (m/z): 277.1/278.1 [M+H]+/[M+2H]+
Reaction SMILES: [I-].[Na+].[Cl:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[C:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[N:15]1[C:19]([CH2:20]Cl)=[N:18][C:17]([C:22]([OH:24])=[O:23])=[N:16]1)=[O:7].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(O)C>[ClH:3].[Cl:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[C:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[N:15]1[C:19]([CH2:20][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[N:18][C:17]([C:22]([OH:24])=[O:23])=[N:16]1)=[O:7]
Reactant: C1COCCN1
Reactant: O=C(O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: Cl
Product: O=C(O)c1nc(CN2CCOCC2)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1

Procedure:
0.10 g of sodium iodide is added to a mixture of 9.3 g (0.0226 mole) of 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid (see German `Offenlegungsschrift` No. 2,159,527, page 32) and 9.5 g (0.11 mole) of morpholine in 100 ml of ethanol, and the whole is reflux for 2 hours. The reaction mixture is thereupon concentrated in vacuo; the residue is dissolved in water, and 2N hydrochloric acid is added until an acid reaction to Congo red is obtained. The precipitated hydrochloride of the reaction product is extracted twice with 100 ml of methylene chloride each time. After washing with saturated sodium chloride solution, drying over sodium sulphate and concentration by evaporation, the organic extracts yield 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(morpholinomethyl)-1H-1,2,4- triazole-3-carboxylic acid hydrochloride in the form of an amorphous yellow foam, which is used directly for the next step.
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[N:8][CH:9]=[C:10]([NH2:13])[CH:11]=3)[NH:6][N:5]=2)[CH2:3][CH2:2]1.[Cl:14][C:15]1[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[CH:22][CH:21]=[C:20]([F:31])[C:16]=1[C:17](O)=[O:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[Cl:14][C:15]1[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:26])=[O:27])=[CH:22][CH:21]=[C:20]([F:31])[C:16]=1[C:17]([NH:13][C:10]1[CH:11]=[C:12]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[N:5][NH:6][C:7]2=[N:8][CH:9]=1)=[O:18]
Reactant: Nc1cnc2[nH]nc(C3CC3)c2c1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(C4CC4)c3c2)c1Cl
Reaction time: 24 h
Yield: 66.3 %

Procedure:
3-Cyclopropyl-1H-pyrazolo[3,4-b]pyridin-5-amine (0.0744 g, 0.427 mmol), 2-chloro-6-fluoro-3-(propylsulfonamido)benzoic acid (0.139 g, 0.470 mmol), EDCI (0.0901 g, 0.470 mmol), and HOBt (0.0635 g, 0.470 mmol) were dissolved in DMF (2 mL) and stirred for 24 hours. The reaction mixture was diluted with ethyl acetate and washed with water (4 X), saturated aqueous sodium bicarbonate solution (2×), and brine, dried over sodium sulfate and concentrated. The crude product was triturated with 1:1 DCM/Et2O to afford 2-chloro-N-(3-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-6-fluoro-3-(propylsulfonamido)benzamide (128 mg, 66% yield) as a solid. 1H NMR (400 MHz, d6-DMSO) 813.21 (s, 1H), 11.08 (s, 1H), 9.74 (s, 1H), 8.66 (s, 1H), 8.55 (s, 1H), 7.59-7.63 (m, 1H), 7.40-7.46 (m, 1H), 3.11-3.15 (m, 2H), 2.29-2.31 (m, 1H), 1.79-1.80 (m, 2H), 0.95-1.00 (m, 7H); MS (APCI-neg) m/z=452.2, 454.1 (M+H).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41](=[O:50])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=1>C1COCC1.ClCCl>[Br:1][CH:42]([C:43]1[CH:44]=[CH:45][C:46]([Cl:49])=[CH:47][CH:48]=1)[C:41]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[Cl:34])=[O:50]
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccccc1Cl
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(c1ccccc1Cl)C(Br)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
29.54 g of phenyltrimethylammonium tribromide are added to a solution of 20.83 g of 1-(2-chlorophenyl)-2-(4-chlorophenyl)ethanone in THF. The homogeneous solution is stirred at room temperature for 1 hour 15 minutes. The reaction medium is filtered and concentrated to dryness. The crude reaction product is taken up in dichloromethane and washed successively with water, with aqueous Na2CO3 solution and then with water. The organic phase is dried over Na2SO4, filtered and concentrated to dryness by distilling off the solvent under reduced pressure. The product is obtained in the form of an oil that crystallizes slowly. The crystals are washed with a minimum amount of ethanol to give the expected product.