Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:35]=[CH:34][O:33][CH:32]=4)[CH2:28][CH2:27][C:26]([C:36]([OH:38])=O)=[CH:25][C:24]=3[CH:39]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:35]=[CH:34][O:33][CH:32]=4)[CH2:28][CH2:27][C:26]([C:36]([NH:29][C:23]4[CH:24]=[CH:39][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:38])=[CH:25][C:24]=3[CH:39]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccoc2)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccoc2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(3-furylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (200 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (155 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (25 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (115 mg) and triethylamine (526 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature for 4.5 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(3-furylmethyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 62) (125 mg) as yellow crystals.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]([CH3:28])([CH2:15][N:16]1[N:20]=[C:19]2[C:21]([Cl:27])=[CH:22][C:23]([Cl:26])=[C:24]([Cl:25])[C:18]2=[N:17]1)[C:13]#[N:14]>C1COCC1>[C:13]([C:12]([NH:11][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1)([CH3:28])[CH2:15][N:16]1[N:20]=[C:19]2[C:21]([Cl:27])=[CH:22][C:23]([Cl:26])=[C:24]([Cl:25])[C:18]2=[N:17]1)#[N:14]
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CC(N)(C#N)Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(I)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-iodobenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,5,7-trichloro-2H-benzotriazol-2-yl)-propionitrile (0.075 mmole, described in Example 39) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (3.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=534, RT=0.73 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:21][C:22]1[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>CS(C)=O.C(OCC)(=O)C>[Cl:21][C:22]1[CH:29]=[C:28]([CH:27]=[CH:26][C:23]=1[C:24]#[N:25])[O:30][C:8]1[CH:7]=[CH:6][C:5]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)(=[O:12])=[O:11])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: N#Cc1cc(S(=O)(=O)Nc2ccc(F)cn2)ccc1F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Oc2ccc(S(=O)(=O)Nc3ccc(F)cn3)cc2C#N)cc1Cl
Temperature: 80 °C
Reaction time: 44 h
Yield: 45.7 %

Procedure:
3-Cyano-4-fluoro-N-(5-fluoropyridin-2-yl)benzenesulfonamide (Preparation 2, 10.5 g, 35.6 mmol) was added to a solution of 2-chloro-4-hydroxybenzonitrile (8.19 g, 53.3 mmol) and potassium carbonate (14.74 g, 106.7 mmol) in dimethylsulfoxide (100 mL) at room temperature. The resulting mixture was stirred at 80° C. for 44 hours. On cooling, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution (200 mL) and ethyl acetate (1000 mL) was added. The aqueous layer was separated and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (3×200 mL), water (2×200 mL) and brine (2×200 mL). The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by reverse phase column chromatography eluting with acetonitrile (containing 0.1% HCO2H): water (containing 0.1% HCO2H) from 0 to 100% to afford the title compound as a white solid (6.982 g, 46%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][CH3:11])=[N:6][C:7]=1[O:8][CH3:9].C(O[CH:15]=[C:16]([C:22]([O:24]CC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[I:1][C:2]1[CH:3]=[C:4]2[C:5](=[N:6][C:7]=1[O:8][CH3:9])[N:10]([CH3:11])[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]2=[O:24]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CNc1ccc(I)c(OC)n1
Product: CCOC(=O)c1cn(C)c2nc(OC)c(I)cc2c1=O
Temperature: 140 °C
Yield: 16 %

Procedure:
6-Methoxy-N-methyl-2-pyridinamine (17.24 g, 124 mmol) is dissolved in DMF (160 mL) and cooled to 0° C. followed by the addition of NIS (28 g, 124 mmol, 1 equiv), at a rate which keeps the reaction temperature below 10° C. The reaction is then allowed to warm to room temperature and stirred for 1 h. The reaction is distilled to dryness in vacuo and the residue is dissolved in CH2Cl2 and passed through a silica plug eluting with heptane/EtOAc (9/1) affording 32 g of crude 5-iodo-6-methoxy-N-methyl-2-pyridinamine. The crude 5-iodo-6-methoxy-N-methyl-2-pyridinamine is dissolved in diethyl ethoxymethylenemalonate (32 mL) and the mixture is heated at 140° C. for 2 h, then cooled to room temperature and passed through a silica plug eluting with heptane/EtOAc (19/1, 0/1). The product is then dissolved in Eaton's reagent (132 mL) and heated at 100° C. for 40 min, cooled to rt and poured into Na2CO3. The basic aqueous layer is then extracted with CH2Cl2 (3×), washed with water, and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (heptane/EtOAc, 4/1, 1/1, CH2Cl2/MeOH 19/1) the desired product is then triturated with MeOH to afford 7.9 g (16%) of ethyl 6-iodo-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate. Physical characteristics are as follows: 1H NMR (CDCl) δ9.04, 8.52, 4.41, 4.13, 3.91, 1.43; IR (diffuse reflectance) 2491, 2427, 2350, 2282, 2242, 1678, 1632, 1613, 1579, 1384, 1309, 1275, 1227, 1106, 804, cm−1; MS (EI) m/z 388, 344, 343, 317, 316, 185, 159, 86, 84, 51; Anal calcd for C13H13IN2O4: C, 40.23; H, 3.38; N, 7.22. Found: C, 40.20; H, 3.40; N, 7.16
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[CH:9]=[CH:10][C:11]([O:13][C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:12][C:7]=2[O:6][C:5](=[O:19])[C:4]=1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[C:22]=1[F:30].[F-:31].[K+].C1OCCOCCOCCOCCOCCOC1.Cl>C(#N)C>[F:31][CH2:2][C:3]1[C:8]2[CH:9]=[CH:10][C:11]([O:13][C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:12][C:7]=2[O:6][C:5](=[O:19])[C:4]=1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[C:22]=1[F:30]
Reactant: CN(C)C(=O)Oc1ccc2c(CBr)c(Cc3cccc([N+](=O)[O-])c3F)c(=O)oc2c1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [K+]
Solvent: CC#N
Product: CN(C)C(=O)Oc1ccc2c(CF)c(Cc3cccc([N+](=O)[O-])c3F)c(=O)oc2c1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
Acetonitrile (1.0 mL) was added to dimethylcarbamic acid 4-bromomethyl-3-(2-fluoro-3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester (compound 6b-1-4) (24.0 mg), and potassium fluoride (3.1 mg) and 18-crown-6 (13.2 mg) were added to the resultant suspension while stirring at room temperature. The mixture was stirred at 60° C. for 4 hours, potassium fluoride (3.1 mg) and 18-crown-6 (13.2 mg) were then added to the reaction solution, and the mixture was further stirred at 60° C. for 1.5 hours. This reaction solution was poured into 1N hydrochloric acid (0.110 mL) diluted with ice water (20 mL), and then extracted with ethyl acetate. The resultant organic layer extraction liquid was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the resultant residue was purified by thin layer silica gel chromatography (hexane:ethyl acetate=1:1) to yield the title compound (14.7 mg).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[CH:14][CH:13]=2)=[N:3]1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CCc1ccc(-c2nc(=O)c3ccccc3s2)nc1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCc1ccc(-c2nc(=O)c3ccccc3s2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
tert-Butyl 3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-3-pyridyl]propanoate (0.21 g, 0.56 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred at room temperature for 0.5 hr. Diisopropyl ether was added to the reaction mixture to give crystals, which were recrystallized from ethanol to give the titled compound (0.12 g, 68%) as white crystals.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Si:7]([O:14][C@@H:15]1[CH2:20][CH2:19][C@H:18]([C:21](OC)=[O:22])[CH2:17][CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[OH-].[K+]>COC(C)(C)C.O>[Si:7]([O:14][C@@H:15]1[CH2:16][CH2:17][C@H:18]([CH2:21][OH:22])[CH2:19][CH2:20]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: COC(=O)[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](CO)CC1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
2.8 g (73.96 mmol) of lithium aluminum hydride are initially charged in 250 ml of tert-butyl methyl ether, and a solution of 22.9 g (84.05 mmol) of the compound from Example 52A in 250 ml of tert-butyl methyl ether is added dropwise at RT. The mixture is stirred at 40° C. for 16 h. A further 0.7 g (18.44 mmol) of lithium aluminum hydride is then added and the reaction mixture is heated at reflux for 10 h. After cooling to RT 20 ml of water are added carefully. 20 ml of a 15% strength solution of potassium hydroxide in water are then added. The phases are separated, the organic phase is dried over sodium sulfate and the solvent is removed on a rotary evaporator. The product obtained is used in the next reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:16][NH2:17])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[O:18]([CH2:25]CO)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([CH2:25][CH2:14][O:13][C:11](=[O:12])[C:10]([NH:16][NH2:17])([CH3:15])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C(C)(Cc1ccc(O)c(O)c1)NN
Reactant: OCCOc1ccccc1
Product: CC(Cc1ccc(O)c(O)c1)(NN)C(=O)OCCOc1ccccc1

Procedure:
Following the procedure described in Example 4 Step A for preparation of compound 107, and substituting methanol with 2-phenoxy-ethanol, provided the title compound. 1H NMR (CD3OD, 400 MHz): 1.65 (s, 3H), 3.10 (dd, 2H), 4.40 (t, 2H), 4.70 (t, 2H), 6.60–6.52 (m, 8H). MS (ESI) m/z 347.27 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:28][CH3:29])=[C:17]([O:20][CH2:21][CH2:22][NH:23][CH2:24][C@@H:25]([OH:27])[CH3:26])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(C(C)C)C(C)C)C.Br[CH2:40][C:41](OC)=[O:42].C(OCCCC)(=O)C>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:28][CH3:29])=[C:17]([O:20][CH2:21][CH2:22][N:23]4[CH2:24][C@H:25]([CH3:26])[O:27][C:41](=[O:42])[CH2:40]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCNC[C@H](C)O
Reactant: COC(=O)CBr
Solvent: O
Solvent: CCCCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCN1CC(=O)O[C@@H](C)C1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
425 g of (S)-4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[(2-hydroxypropyl)amino]ethyloxy}-7-methoxy-quinazoline and 210 ml N-ethyl-diisopropylamine are dissolved in 640 ml N-methylpyrrolidone. After the addition of 105 ml methyl bromoacetate the mixture is stirred for 1 hour at 20–25° C. After the addition of 8500 ml n-butyl acetate and 4300 ml of water the phases are separated and the organic phase is washed with 4300 ml of water. The organic phase is evaporated down at 200 mbar to 50% of the original volume and 4300 ml of n-butyl acetate are added. The mixture is heated to 120–130° C. for 40 hours, filtered and evaporated down to a volume of 2000 ml at 200 mbar. After cooling to −10° C. the precipitate is suction filtered, washed with 800 ml n-butyl acetate and dried at 50° C. The crude product is recrystallised twice from methylethylketone (3750 and 5100 ml).
Reaction SMILES: C(C(CCCC)C=O)C.O=O.[CH2:12]([CH:14]([CH2:18][CH2:19][CH2:20][CH3:21])[C:15]([O-:17])=[O:16])[CH3:13].[K+].[OH-].[K+]>>[CH2:12]([CH:14]([CH2:18][CH2:19][CH2:20][CH3:21])[C:15]([OH:17])=[O:16])[CH3:13]
Reactant: CCCCC(CC)C(=O)[O-]
Agent: CCCCC(C=O)CC
Agent: O=O
Agent: [K+]
Product: CCCCC(CC)C(=O)O
Yield: 96 %

Procedure:
12.82kg/h of 2-ethylhexanal and 1.79kg/h of oxygen (molar ratio 1:0.56) were caused to react in the presence of 1.9wt% of potassium 2-ethylhexanoate (prepared by the addition of KOH to the initial reaction mixture) at 40° C. and a pressure of 3 bar. 96 % of 2-ethylhexanoic acid having a color value of 4 were isolated by distillation (determined as specified in ISO 6271 ). The bottoms were recycled to the oxidation stage.
Reaction SMILES: C(O)C.[CH:4]1([C:7](=O)[CH2:8][C:9](=O)[CH3:10])[CH2:6][CH2:5]1.[C:13]([CH2:15][C:16]([NH2:18])=[O:17])#[N:14].N1CCCCC1>O>[CH:4]1([C:7]2[NH:18][C:16](=[O:17])[C:15]([C:13]#[N:14])=[C:9]([CH3:10])[CH:8]=2)[CH2:6][CH2:5]1
Reactant: N#CCC(N)=O
Reactant: CC(=O)CC(=O)C1CC1
Solvent: CCO
Solvent: C1CCNCC1
Solvent: O
Product: Cc1cc(C2CC2)[nH]c(=O)c1C#N
Temperature: 75 °C

Procedure:
To a stirring solution of ethanol (5 mL) were suspended 1-cyclopropyl-1,3-butanedione (505 mg, 3.00 mmol) and cyanoacetamide (252 mg, 3.00 mmol), and the heterogenous contents heated until homogenous (ca. 75° C.). Next added piperidine (0.395 mL, 4.00 mmol), and the mixture was stirred with warming at reflux for 30 min. The reaction mixture was allowed to cool to room temperature, wherein precipitation ensued. The solid precipitate was filtered and set aside. The filtrate was concentrated in vacuo, and the oily residue treated with minimal EtOAc and then 10 mL hexanes to afford a 2nd crop of solid. The solid product crops were combined, suspended in water (7 mL), vigorously stirred, and vacuum filtered to afford a nearly white solid as 380 mg (73%). LCMS E-S (M+H)=175.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.01-1.09 (m, 2 H), 1.28 (dd, J=8.59, 2.27 Hz, 2 H), 1.95-2.01 (m, 1H), 2.43 (s, 3H), 5.82 (s, 1 H).
Reaction SMILES: C(O[C:4](=[O:17])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)C.O.[F:19][C:20]([F:25])([F:24])[CH2:21][NH:22][NH2:23]>C(O)(=O)C.O>[F:19][C:20]([F:25])([F:24])[CH2:21][N:22]1[C:4](=[O:17])[CH2:5][C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)=[N:23]1
Reactant: CCOC(=O)CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: NNCC(F)(F)F
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC(c2cccc([N+](=O)[O-])c2)=NN1CC(F)(F)F

Procedure:
0.15 Mole (35.6 g) of m-nitrobenzoyl acetic acid ethyl ester and 0.15 mole (25.2 g) of 2,2,2-trifluoroethyl hydrazine hydrate were stirred together for 2 hours in 90 ml of boiling acetic acid. Subsequently, the reaction mixture was poured out in water. After stirring and filtration, the precipitate was recrystallized from methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([NH2:15])=[O:14])=[CH:9]2)([O-:3])=[O:2].[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>N1C=CC=CC=1>[Br:16][C:9]1[C:8]2[C:12](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[NH:11][C:10]=1[C:13]([NH2:15])=[O:14]
Reactant: [Br-]
Reactant: NC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: NC(=O)c1[nH]c2c([N+](=O)[O-])cccc2c1Br
Temperature: 0 °C
Reaction time: 16 h
Yield: 78.9 %

Procedure:
A suspension of 2.57 g (12.53 mmol) of 7-nitro-1H-indole-2-carboxamide in 35 ml of pyridine is cooled to 0° C. in a water/ice bath. A solution of 4.01 g (12.53 mmol) of pyridinium tribromide in 20 ml of pyridine is then added at 0° C. dropwise, and the reaction is then stirred at 0° C. for 30 minutes and at ambient temperature for 16 h. 70 ml of ice-cold water are then added to the reaction medium. The latter is then stirred at ambient temperature for 15 minutes and is then filtered over sintered glass, to give 2.81 g of 3-bromo-7-nitro-1H-indole-2-carboxamide in the form of a brown solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClCC1[O:49][N:48]=[C:47]([CH3:50])[N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[O:49][N:48]=[C:47]([CH3:50])[N:46]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Cc1noc(CCl)n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cc1noc(Cn2nnc3c(N4CCC(F)(F)C4)nc(C(C)(C)C)nc32)n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole and isolated as light-yellow gum. MS (m/e): 379.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)([OH:14])[C:6]=2[CH:21]=1.[H-].[Na+].[CH3:24]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]([O:14][CH3:24])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:21]=1
Reactant: CC1(C)COc2ccc(Br)cc2C(O)(c2ccccn2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2ccccn2)CC(C)(C)COc2ccc(Br)cc21
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A solution of 7-bromo-3,3-dimethyl-5-(2-pyridyl)-benzoxepin-5-ol (5 g, 0.014 mol) in anhydrous DMF (50 ml) is added dropwise to a suspension of sodium hydride (50% dispersed in oil, 0.8 g, 0.0168 mol) in anhydrous DMF (25 ml), the temperature rises to 88° C., stirring is continued for 1 hour and the reaction mixture is maintained at 80° C. A solution of methyl iodide (1.9 g, 0.014 mol) in anhydrous DMF (10 ml) is then added dropwise at 25° C.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[CH:12]1([N:18]([CH2:52][CH:53](OC)[O:54]C)[C:19](=[O:51])[CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][N:32]3[CH2:50][CH2:49][C:35]4([O:40][CH2:39][CH2:38][N:37]([C:41]([C:43]5[N:44]=[C:45]([CH3:48])[S:46][CH:47]=5)=[O:42])[CH2:36]4)[CH2:34][CH2:33]3)[CH:26]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:12]1([N:18]([CH2:52][CH:53]=[O:54])[C:19](=[O:51])[CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][N:32]3[CH2:50][CH2:49][C:35]4([O:40][CH2:39][CH2:38][N:37]([C:41]([C:43]5[N:44]=[C:45]([CH3:48])[S:46][CH:47]=5)=[O:42])[CH2:36]4)[CH2:34][CH2:33]3)[CH:26]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC(CN(C(=O)CCOCCc1cccc(CN2CCC3(CC2)CN(C(=O)c2csc(C)n2)CCO3)c1)C1CCCCC1)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)N(CC=O)C5CCCCC5)c4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tosic acid (1384 mg) was added to a solution of N-cyclohexyl-N-(2,2-dimethoxyethyl)-3-(3-((4-(2-methylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanamide (Example 277, step c) (683 mg) in DCM (10 mL) and the resulting mixture stirred at ambient temperature for 4 h. Sodium bicarbonate solution (saturated, 10 mL) was cautiously added and the mixture stirred until bubbling ceased (10 min). The reaction was diluted with DCM (50 mL) and the aqeuous separated. The organic was washed with saturated sodium bicarbonate solution (2×20 mL), brine (20 mL), dried over sodium sulphate, filtered and evaporated to afford the subtitled compound.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH2:6]1)(=[O:4])=[O:3].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(=S)=S.C(Cl)Cl.O>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([Cl:21])=[CH:23][CH:24]=3)=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N1CC(c2cccc(Cl)c2)c2ccccc21
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: S=C=S
Product: CS(=O)(=O)N1CC(c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Reaction time: 2 h

Procedure:
To a solution of 1-methylsulfonyl-3-(3-chlorophenyl)indoline (4.40 g, 14.3 mmol, see Preparation 5) and 4-chlorobenzoyl chloride (3.25 g, 18.6 mmol) in CS2 (25 mL) was added portionwise AlCl3 (7.62 g, 57.2 mmol) at about 0° C. A brown precipitate formed immediately. The mixture was stirred for about 2 hours. To the mixture was added slowly 100 mL of cold water containing 3 mL of concentrated HCl. The solution was diluted with DCM and the organic layer was separated and washed with 1N HCl aqueous solution (2 times), saturated NaHCO3 aqueous solution (2 times) and brine (2 times), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluting with EtOAC/hexane 1:2. The title compound was obtained as a solid. Yield=3.90 g, 61%. Rf=0.24 (silica, EtOAc/hexane 1:2). MS (ES): 445.2; Calc. MW=445.4, 1H NMR (300 MHz, CDCl3) δ: 7.67-7.76 (m, 3H), 7.53-7.59 (m, 2H), 7.48 (s, 1H), 7.44 (s, 1H), 7.30-7.32 (m, 2H), 7,20 (m, 1H), 7.09-7.14 (m, 1H), 4.65 (t, 1H), 4.50 (t, 1H), 3.98 (dd, 1H), 3.02 (s, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([NH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]([CH2:19][CH2:20][CH2:21][CH3:22])[O:14][C:15]2=[O:16])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]>>[C:5]([NH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]([CH2:19][CH2:20][CH2:21][CH3:22])[O:14][C:15]2=[O:16])=[CH:11][C:10]=1[N+:1]([O-:4])=[O:2])(=[O:7])[CH3:6]
Reactant: CCCCC1OC(=O)c2cc(NC(C)=O)ccc21
Reactant: O=[N+]([O-])O
Product: CCCCC1OC(=O)c2cc(NC(C)=O)c([N+](=O)[O-])cc21
Reaction time: 8 h

Procedure:
To 100 ml of stirred and ice-cold turning nitric acid (sp. gr. 1.50) there are added, in portions, 59 g (0.288 mol) of compound obtained in Example 7 with the temperature below 10° C. The resulting clear solution is put aside at room temperature overnight. The reaction material is poured into crushed ice, and the solid is filtered, washed with water, dried and crystallised from ethanol, giving the title compound.