Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:24]([OH:25])=[CH:23][CH:22]=[C:21]([F:26])[C:3]=1[NH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:13]=1)[C:9]#[N:10].C([O-])([O-])=O.[K+].[K+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].O>CN(C=O)C>[C:9]([C:8]1[CH:7]=[C:6]([CH2:5][NH:4][C:3]2[C:2]([F:1])=[C:24]([CH:23]=[CH:22][C:21]=2[F:26])[O:25][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:11]=1)#[N:10]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1cc(CNc2c(F)ccc(O)c2F)cc(-c2cccc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(C#N)cc(-c3cccc(F)c3)c2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a solution of 3-[(2,6-Difluoro-3-hydroxy-anilino)methyl]-5-(3-fluorophenyl)benzonitrile (280 mg, 0.8 mmol, 1 eq) in DMF (10 mL) was added K2CO3 (550 mg, 4 mmol, 5 eq). The solution was stirred at room temperature for 30 min, then ethyl bromoacetate (200 mg, 1.2 mmol, 1.5 eq) was added dropwise. The reaction was stirred overnight, then water was added and the aqueous phase extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 15:1) to give the title compound as colorless oil (300 mg, 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:4][CH:3]=1.[CH2:28](O)[CH3:29].S(=O)(=O)(O)O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:28][CH3:29])=[O:24])=[CH:26][CH:27]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccccn3)[nH]2)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccccn3)[nH]2)cc1

Procedure:
Material from Example 3 was heated at reflux in a solution of ethanol/sulfuric acid for 18 h. The solution was concentrated to removed the ethanol and the resulting aqueous solution was extracted with chloroform to yield the title compound. ESMS (M+H)+=388.2.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].[N+:9]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O)([O-:11])=[O:10].O=[C:21]([CH3:30])[CH2:22][C:23]([O:25][CH2:26][CH2:27][C:28]#[N:29])=[O:24]>>[CH3:8][C:2]1[NH:1][C:21]([CH3:30])=[C:22]([C:23]([O:25][CH2:26][CH2:27][C:28]#[N:29])=[O:24])[CH:15]([C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(=O)CC(=O)OCCC#N
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCC#N)C1c1cccc([N+](=O)[O-])c1

Procedure:
Compounds of formula 1 may also be prepared via Scheme IV. A dihydropyridine of formula 12 is prepared as in Scheme I, and the compound condensed with an intermediate of formula 9 to form a compound of formula 1. For example, methyl 3-aminocrotonate, 3-nitrobenzaldehyde, and 2-cyanoethyl 3-oxobutanoate are heated together to form 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(2-cyano)ethoxycarbonyl-1,4-dihydropyridine. The cyanoethyl ester is hydrolyzed using NaOH followed by HCl, converted to an acid halide (e.g., using thionyl chloride), and condensed with a compound of the formula HO--A--X, for example, 3-bromopropanol, to form a compound of formula 12. For example, 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(2-cyano)ethoxycarbonyl-1,4-dihydropyridine is treated sequentially with NaOH, HCl, and thionyl chloride, then condensed with 3-bromopropanol to form 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(3-bromopropoxycarbonyl)-1,4-dihydropyridine (12). The resulting bromo derivative is then condensed with 4-(2-tetrahydropyran-2-yloxyethyl)phenol to form 2,6 -dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(3-[4-(2-tetrahydropyran-2-yloxyethyl)phenyl]propoxycarbonyl)-1,4-dihydropyridine (1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:12]([OH:14])=O.Cl.Cl.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][CH2:33][CH2:34][NH2:35])=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:12]([NH:35][CH2:34][CH2:33][NH:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=1)=[O:14]
Reactant: COc1ccc(NCCN)cc1
Reactant: O=C(O)[C@H](CC1CCCCC1)Nc1nc2ccccc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(NCCNC(=O)[C@H](CC2CCCCC2)Nc2nc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.7 %

Procedure:
To a stirring solution of 2-(S)-(benzooxazol-2-ylamino)-3-cyclohexyl propionic acid (288 mg, 1.0 mmol), N1-(4-methoxy-phenyl)-ethane-1,2-diamine-2HCl (239 mg, 1.0 mmol), and iPr2NEt (0.87 mL, 5.0 mmol) in dichloromethane (4 mL) was added HATU (418 mg, 1.1 mmol). The solution was stirred at room temperature for 4 hours and then evaporated to dryness. The crude material was chromatographed over silica gel (Hexanes/EtOAc) to afford the title compound as a white powder (243 mg, 56%). HPLC-MS calcd. for C25H32N4O3 (M+H+) 437.25, found 437.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18](S(C)(=O)=O)[N:17]=2)[CH:13]=[CH:12][S:11]3)=[CH:4][CH:3]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].CCN(C(C)C)C(C)C.O>CS(C)=O>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:18]2[N:17]=[C:16]([C:15]3[N:14]4[C:10]([S:11][CH:12]=[CH:13]4)=[N:9][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:21]=[CH:20][N:19]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)nc3sccn23)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2nccc(-c3c(-c4ccc(F)cc4)nc4sccn34)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 6-(4-fluorophenyl)-5-(2-methanesulfonyl-pyrimidin-4-yl)-imidazo[2,1-b]thiazole (L) (1.05 g, 2.8 mmol) in dimethylsulfoxide (12.0 mL) is added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.12 g, 5.6 mmol) followed by Hunig's Base (0.76 mL, 5.6 mmol). The reaction mixture is sealed and set to shake at 100° C. for 12 hours. After cooling to room temperature, water is added (50 mL) and the aqueous phase extracted with ethyl acetate (4×20 mL). The combined organic phase is washed with a saturated, aqueous, sodium chloride solution (3×50 mL) and dried over anhydrous sodium sulfate. The organic phase is filtered and the solvent evaporated in vacuo. The crude product is purified by silica gel column chromatography eluting with ethyl acetate/hexane (3/2). The compound 4-{4-[6-(4-fluorophenyl)-imidazo[2,1-b]thiazol-5-yl]-pyrimidin-2-ylamino}-piperidine-1-carboxylic acid tert-butyl ester (M) (Compound CCXXXIII, Table 2) is obtained as a light yellow solid (1.2 g, 88%); m.p. 209-211° C.;
Reaction SMILES: [C:1]1([CH2:11][N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:25])[C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][C:17]=3[C:26](=[O:28])[NH2:27])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C.C(OCC)(=O)C>[C:1]1([CH2:11][N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([O:25][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][C:17]=3[C:26](=[O:28])[NH2:27])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc2ccccc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc2ccccc12
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
40% Methanolic Triton B (0.2 mL, 0.26 mM) was added to a solution of the 9-[(1-naphthyl)methyl]-4-hydroxy-5-carbamoyl carbazole (80 mg, 0.22 mM) in 7 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (40 mg, 0.3 mM) was added and the resultant mixture stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate, washed twice with H2O, and once with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 81 mg (85%) of the {9-[(1-naphthyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDCl3) δ8.2 (d, 1H, J=8 Hz), 8.05 (d, 1H, J=8 Hz), 7.85-7.0 (m, 11H), 6.65 (d, 1H, J=8 Hz), 6.3 (d, 1H, J=8 Hz), 6.2 (s, 2H), 4.95 (s, 2H), and 3.8 (s, 3H). IR (KBr, cm−1) 3364, 1739, 1630, 1582, 1500, 1455, 1285, 1232, 1153, and 774. MS (FD) m/e 438.
Reaction SMILES: [Br:1]Br.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:6]=2[CH2:5][CH2:4]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:8]1[C:7]2[O:3][CH2:4][CH2:5][C:6]=2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=1
Reactant: CCOC(=O)CCc1ccc2c(c1)CCO2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)CCc1cc(Br)c2c(c1)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
Bromine (10.5 g, 65.8 mmols) was dropwise added to an acetic acid (150 ml) solution containing ethyl 3-(2,3-dihydrobenzofuran-5-yl)propionate (14.5 g, 65.8 mmols) and sodium acetate (5.94 g, 72.4 mmols), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, which was then extracted with ethyl acetate. The extract was washed with a saturated saline solution and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure to obtain 19.2 g (yield: 97%) of the target compound. This was oily.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:27])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][C:19]3[C@H:21]([CH2:25][OH:26])[NH:22][C:23](=[O:24])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].[C:28](NC1C(C)=NC2C(N=1)=C(C1NC3[C@@H](CO)NC(=O)C=3C=1)C=CC=2)(C)(C)C.[H-].[Na+].CI>C1COCC1.CN(C=O)C>[C:1]([NH:5][C:6]1[C:7]([CH3:27])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[N:20]([CH3:28])[C:19]3[CH:21]([CH2:25][OH:26])[NH:22][C:23](=[O:24])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)[C@@H](CO)NC4=O)c2nc1NC(C)(C)C
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)[C@H](CO)NC4=O)c2nc1NC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1nc2cccc(-c3cc4c(n3C)C(CO)NC4=O)c2nc1NC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a 25-mL round-bottomed flask was added (R)-2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6-(hydroxymethyl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one and (S)-2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6-(hydroxymethyl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (469) (36 mg, 0.1 mmol), DMF (1 mL) and THF (1 mL). To the yellow suspension NaH (4 mg, 0.1 mmol, 60% in mineral oil) was added at RT. The reaction mixture was stirred at RT for 15 min and MeI (6 μt, 0.1 mmol) was added. The reaction mixture was stirred at RT for 1 h and the solvent was completely removed under vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 3-8% MeOH in DCM to provide 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6-(hydroxymethyl)-1-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (470) (28 mg, 75% yield, 50% ee) as a light yellow solid and a mixture of enantiomers. 1H NMR (400 MHz, DMSO-d6) δ 7.78 (dd, J=1.47, 8.12 Hz, 1H), 7.43-7.51 (m, 2H), 7.33-7.39 (m, 1H), 6.10 (s, 1H), 5.88 (s, 1H), 5.15 (t, J=5.38 Hz, 1H), 4.46 (t, J=6.16 Hz, 1H), 3.59 (t, J=5.97 Hz, 2H), 3.32 (s, 3H), 2.52 (s, 3H), 1.29 (s, 9H). m/z (ESI, +ve) 380.1 (M+H)+.
Reaction SMILES: N[CH2:2][C:3]([NH:6][C:7]([C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:19]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=4)=[N:22][N:21]4[CH2:31][CH2:32][CH2:33][C:20]=34)=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)=[O:8])([CH3:5])[CH3:4].[C:34]([BH3-])#[N:35].[Na+].[C:38](O)(=O)C.C=O>CO>[CH3:38][N:35]([CH3:34])[CH2:2][C:3]([NH:6][C:7]([C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:19]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=4)=[N:22][N:21]4[CH2:31][CH2:32][CH2:33][C:20]=34)=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: Cc1cccc(-c2nn3c(c2-c2ccnc4cc(C(=O)NC(C)(C)CN)ccc24)CCC3)n1
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(-c2nn3c(c2-c2ccnc4cc(C(=O)NC(C)(C)CN(C)C)ccc24)CCC3)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic acid(2-amino-1,1-dimethyl-ethyl)-amide (0.12 g, 0.27 mmol), sodium cyanoborohydride (0.038 g, 0.6 mmol), and acetic acid (0.077 mL, 1.3 mmol) in methanol (5 mL) is cooled to 0° C. and stirred for 10 min. A solution of 37% aqueous formaldehyde (0.086 mL, 3.1 mmol) in methanol (2 mL) is added dropwise. The mixture is allowed to warm to room temperature and stirred for 1 h. The reaction is quenched with saturated aqueous potassium carbonate solution and concentrated in vacuo. The residue is taken up in chloroform, washed with water and brine, dried (sodium sulfate) and concentrated in vacuo. The residue is chromatographed on SiO2 (8% methanol/92% dichloromethane) to yield the title compound, 33 mg (27%), as a white foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]([NH2:19])=[S:18])=[N:11][CH:12]=[C:13]([Br:15])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][C:22](=O)[CH3:23].C(N(CC)CC)C>C(O)C>[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:21]=[C:22]([CH3:23])[N:19]=2)=[N:11][CH:12]=[C:13]([Br:15])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1ncc(Br)nc1OCc1ccccc1
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1csc(Nc2ncc(Br)nc2OCc2ccccc2)n1
Yield: 30.7 %

Procedure:
Following the method of Example 1, Step D, 1-(3-(benzyloxy)-5-bromopyrazin-2-yl)thiourea (952 mg, 2.81 mmol), 1-chloropropan-2-one (364 mg, 3.93 mmol) and triethylamine (0.655 mL, 4.77 mmol) were reacted in ethanol (10 mL) to provide N-(3-(benzyloxy)-5-bromopyrazin-2-yl)-4-methylthiazol-2-amine (325 mg, 31%) as a light tan powder. 1H NMR (d6-DMSO) δ 8.01 (s, 1H), 7.57 (d, 2H), 7.35-7.43 (m, 3H), 6.62 (s, 1H), 5.42 (s, 2H), 2.32 (s, 3H). Mass spectrum (apci) m/z=377 (100), 379 (97) (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:26]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CO>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:26]4[CH:27]=[CH:28][C:29]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:30][C:25]=4[F:24])[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4F)ncc3o2)CC1

Procedure:
A mixture of 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (100 mg), 2-fluoro-4-(methanesulfonyl)phenylboronic acid (97 mg), 2 M aqueous Na2CO3 solution (0.33 mL), methanol (0.5 mL), and 1,4-dioxane (1.5 mL) is sparged with Ar for 10 min. PdCl2 [1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (22 mg) is added and the mixture is stirred at reflux temperature for 2 h. The mixture is diluted with water and methanol and purified by HPLC on reversed phase (methanol/water) to give the title compound. LC (method 5): tR=1.29 min; Mass spectrum (ESI+): m/z=475 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-])=O)=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[H][H]>ClCCl.CO.[Pd]>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)N1C(=O)Cc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1C(=O)Cc2cc(N)ccc21

Procedure:
30.0 g (136 mmol) of 1-acetyl-5-nitro-2-indolinone are dissolved in a mixture of 650 ml of dichloromethane and 650 ml of methanol and after the addition of 5 g of 10% palladium on activated charcoal the mixture is hydrogenated for 45 minutes with hydrogen. Then the catalyst is filtered off and evaporated down.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[O:7]1[CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][NH:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.IC>CC(C)=O.ClCCl>[CH3:1][N:10]1[CH2:11][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:7][C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]1=2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1CNc2ccccc2O1
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)C1CN(C)c2ccccc2O1
Temperature: 60 °C
Reaction time: 24 h
Yield: 65.5 %

Procedure:
In a sealable vessel, potassium carbonate (56 mg, 0.41 mmol) was added to a solution of (±)-ethyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (60 mg, 0.29 mmol) and iodomethane (22 □L, 0.35 mmol) in acetone (2 mL). The vessel was sealed and the reaction mixture was stirred at 60° C. for 24 h. The mixture was cooled to ambient temperature, diluted with dichloromethane (60 mL), and the organic layer was extracted with water (10 mL) and half-saturated brine (10 mL). The organic layer was dried over sodium sulfate and concentrated. Purification of the concentrate by flash column chromatography (5% to 10% EtOAc/hexane) afforded the title compound (43 mg, 0.19 mmol). MS m/z: 222 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:17]2[O:16][CH2:15][CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:27][N:28](C=O)C>CCOC(C)=O.O.[C-]#N.[Zn+2].[C-]#N.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>[C:27]([C:7]1[C:17]2[O:16][CH2:15][CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)#[N:28]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2OS(=O)(=O)C(F)(F)F)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCOc2c(C#N)cccc2C1

Procedure:
A solution of 1,1-dimethylethyl 9-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 63) (9 g, 22.65 mmol), zinc cyanide (3.99 g, 34.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.62 g, 2.265 mmol) in DMF (90 ml) was heated at 80° C. for 24 hrs. The reaction was cooled, diluted with EtOAc (400 ml) and water (400 ml) and filtered to remove insoluble material. The filtrate was separated and the organic layer washed with water, dried over magnesium sulphate and evaporated. Purified by flash chromatography eluting with EtOAc/iso-hexane 1:9 then 1:3 to give the title compound (5.1 g) as a colourless oil. MS (ES): C15H18N2O3 requires 274; found 174 [M+H−100]+.
Reaction SMILES: [ClH:1].[C:2]1([C:8]2([C:18]([O:20]CC)=O)[CH2:10][CH:9]2[CH2:11][N:12]2[CH2:17]COC[CH2:13]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:23]>>[Cl:1][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:8]1([C:18]([NH2:23])=[O:20])[CH2:10][CH:9]1[CH2:11][N:12]([CH3:17])[CH3:13]
Reactant: N
Reactant: Cl
Reactant: CCOC(=O)C1(c2ccccc2)CC1CN1CCOCC1
Product: CN(C)CC1CC1(C(N)=O)c1ccccc1Cl

Procedure:
In a manner similar to that described in Example 1 but hydrolyzing the hydrochloride of 1-orthochlorophenyl 1-ethoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z) and then treating the intermediate acid chloride with ammonia and salifying with hydrochloric acid, there is obtained the product of the formula ##STR17##
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.[B-](F)(F)(F)[F:17].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.O>C1COCC1>[F:17][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=1
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1cc(-c2ccnn2C)cs1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(-c2c(F)cnn2C)cs1
Reaction time: 1 h
Yield: 33 %

Procedure:
A solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (330 mg, 1.49 mmol) and Selectfluor® (793 mg, 2.23 mmol) in THF (7 mL) and H2O (500 uL) was stirred in a sealed tube at 70° C. After 1 h, additional selectfluor (793 mg, 2.23 mmol) was added and the solution stirred an additional 12 h. The reaction mixture was then partitioned between H2O-DCM, the aqueous phase was washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, 20% EtOAc in hexanes) affording the title compound (126 mg, 33%) as a white solid: LCMS (ES) m/z=241 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[N:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:37][C:38]1[S:39][C:40]([CH2:43]Cl)=[CH:41][CH:42]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:22][C:23]1[CH:24]=[N:25][N:26]([CH2:43][C:40]2[S:39][C:38]([Cl:37])=[CH:42][CH:41]=2)[CH:27]=1)[C:28]1[CH:29]=[N:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccc(Cl)s3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 74.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.44 g) and 2-chloro-5-(chloromethyl)thiophene (0.79 g) as starting materials, 5-benzyloxy-N-({1-[(5-chlorothiophen-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.37 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 133, N-({1-[(5-chlorothiophen-2-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.37 g) was obtained. melting point: 98-101° C.