Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:16])[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][C:2]1=O.[F:17][C:18]([F:29])([F:28])[O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)C=O>>[F:17][C:18]([F:28])([F:29])[O:19][C:20]1[CH:27]=[C:26]([CH:13]2[C:14]3[C:1](=[O:16])[CH2:2][CH2:3][CH2:4][C:5]=3[NH:6][C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]2=3)[CH:25]=[CH:22][CH:21]=1
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: O=C1C=Cc2nc3ccccc3cc2C1=O
Product: O=C1CCCC2=C1C(c1cccc(OC(F)(F)F)c1)C1=C(CCCC1)N2

Procedure:
The necessary acridinedione starting material may be prepared following the method described in Example 28 hereinbelow, but using 3-trifluoromethoxybenzaldehyde in place of 3-trifluoromethylbenzaldehyde. M.p. 273°-275° C. Found for C20H18FNO3: . C,63.55; H,4.71; N,3.67.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20]C)=[C:14]([O:22][CH3:23])[CH:13]=3)=[CH:8][CH:9]=2)[C:4]([C:24]#[N:25])=[CH:3]1.C[Si](I)(C)C.O>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:13]=[C:14]([O:22][CH3:23])[C:15]([OH:20])=[C:16]([O:18][CH3:19])[CH:17]=3)=[CH:8][CH:9]=2)[C:4]([C:24]#[N:25])=[CH:3]1
Reactant: COc1cc(Oc2ccc3c(c2)c(C#N)cn3C)cc(OC)c1OC
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: O
Product: COc1cc(Oc2ccc3c(c2)c(C#N)cn3C)cc(OC)c1O
Temperature: 25 °C

Procedure:
To a solution of 1-methyl-3-cyano-5-(3,4,5-trimethoxyphenoxy)-1H-indole (500 mg; 1.47 mmol) in CH2Cl2 (10 ml) was added trimethylsilyl iodide (831 μl; 5.84 mmol). After stirring at room temperature under argon atmosphere for 2 h30, the mixture was poured into cold water, extracted with ethyl acetate. The organic phase was evaporated and the residue was purified by flash chromatography on silica gel, eluting with CH2Cl2/Et2O 1:1 to give 1-methyl-3-cyano-5-(4-hydroxy-3,5-dimethoxyphenoxy)-1H-indole: (244 mg)
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]([CH3:12])=[N:10][CH:11]=2)[N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].BrCCC[CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34]>CN(C=O)C>[CH3:12][C:9]1[N:10]=[CH:11][C:6]([C:4]2[N:3]=[CH:2][N:1]([CH2:23][N:24]3[C:28](=[O:29])[C:27]4[C:26](=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:25]3=[O:34])[CH:5]=2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(-c2c[nH]cn2)cn1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cn(CN3C(=O)c4ccccc4C3=O)cn2)cn1
Temperature: 80 °C
Reaction time: 24 h
Yield: 37 %

Procedure:
To a solution of 5-(1H-imidazol-4-yl)-2-methyl-pyridine (1 eq) in DMF was added potassium carbonate (4 eq) at room temperature under dry conditions. After heating the reaction mixture in a 80° C. oil bath for 1 hour, N-(4-bromobutyl)phtalimide (3.9 eq) was added to the mixture. The solution was left stirring in a 80° C. oil bath for 24 hours. Upon cooling, the reaction was filtered and the solid was washed with ethyl acetate. The filterate was diluted with ethyl acetate and washed with NH4Cl (sat.), H2O, NaCl (sat.), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography using an initial solvent gradient of 97% DCM, 3% MeOH, and 0.1% TEA (1 L) to afford the product (37%). MH+(361)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])[C:5]([Cl:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[C:44]([O:45][CH3:46])=[CH:43][C:28]2[CH2:29][CH2:30][N:31]([CH2:34][C:35]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:36])[CH2:32][CH2:33][C:27]=2[CH:26]=1>>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])=[N:7][C:2]([NH:24][C:25]2[C:44]([O:45][CH3:46])=[CH:43][C:28]3[CH2:29][CH2:30][N:31]([CH2:34][C:35]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[O:36])[CH2:32][CH2:33][C:27]=3[CH:26]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N1CCOCC1)CC2
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCOCC4)cc3OC)n1)CCN(CC(=O)N1CCOCC1)CC2
Yield: 56 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1-morpholin-4-yl-ethanone. Product isolated as white crystals (60 mg, 56%). mp: 189-191° C., MS (ESI+): 638.5 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.27 (d, J=8 Hz, 1H), 8.14 (s, 1H), 8.04 (s, 1H), 7.55 (s, 1H), 7.45 (s, 1H), 6.65 (s, 1H), 6.57 (s, 1H), 6.52 (d, J=8 Hz, 1H), 3.93-3.88 (m, 10H), 3.74-3.67 (m, 8H), 3.29 (s, 2H), 3.16 (t, J=5 Hz, 4H), 2.87 (m, 2H), 2.83 (m, 2H), 2.69 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][N:12]1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[N:22]=1.CN(C)C=O>ClCCl>[ClH:27].[CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:23]1[N:22]=[C:21]([N:12]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]2[CH3:10])[CH:26]=[CH:25][N:24]=1
Reactant: CC1c2ccccc2CCN1c1ccnc(Cl)n1
Reactant: Cc1cc(F)ccc1N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Nc1nccc(N2CCc3ccccc3C2C)n1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Methyl-4-fluoroaniline(1.1 ml, 10.2 mmol) was added to a mixture solution of 4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(1.5 g, 5.8 mmol) and dimethylformamide(10 ml). The reaction mixture was stirred for 3 hours at 110°-120° C., cooled to a room temperature, diluted with dichloromethane, and then washed with water. The dichloromethane layer was separated, basified with aqueous sodium hydroxide, washed with water, dried and concentrated. The resulting residue was crystallized by silica gel column chromatography to give free base form of the titled compound. To a mixture solution of the free base form of the titled compound and ethyl ether was added aqueous hydrochloric acid and the resulting titled compound was filtered and dried in vacuo. Recrystallization from ethanol afforded 1.2 g of the titled compound as a white crystalline solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])=[O:17])[CH2:12][CH2:11]2)[N:3]=1.[CH3:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CC#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.O>[CH3:9][NH:8][C:6]1[N:7]=[C:2]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH3:30])[N:3]=[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:28])([F:29])[F:27])=[O:17])[CH2:12][CH2:11]2)[N:5]=1
Reactant: Cc1ccccc1B(O)O
Reactant: CNc1nc(Cl)nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
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: CC#N
Product: CNc1nc(-c2ccccc2C)nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
Temperature: 90 °C
Yield: 30.4 %

Procedure:
To a suspension of 1-[4-chloro-6-(methylamino)-1,3,5-triazin-2-yl]-N-{[2-(trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide (Intermediate 7d, 75 mg, 0.17 mmol, 1.0 equiv), (2-methylphenyl)boronic acid (29 mg, 0.21 mmol, 1.2 equiv), and Na2CO3 (37 mg, 0.35 mmol, 2.0 equiv) in 3:1 CH3CN:H2O was added Pd(PPh3)4 (10 mg, 0.0088 mmol, 0.05 equiv). The reaction mixture was heated at 90° C. for 1 h. The resulting suspension was filtered through an SCX resin (55 □m, 70 A, 2 g/12 mL giga tubes) using MeOH, and the product was recovered by eluting with 2.0 M NH3 in MeOH. The filtrate was concentrated, and the resulting residue was purified using reverse-phase HPLC (XBridge, 10-80% CH3CN/H2O, 0.1% TFA, 12 min) to afford 25 mg (30%) of the title compound. MS (ES+): m/e 485.2 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:11][C:10]3[CH:19]=[N:20][CH:21]=[CH:22][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23](O)=O.C=O.C(Cl)(Cl)Cl.CCCC(C)C.CCN(CC)CC.CN1CCN(C)C2C=NC=CC1=2.C(N1C2C(CCCC2)N(CC)C2C=NC=CC1=2)C>>[CH3:23][N:11]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:8][C:9]2[CH:22]=[CH:21][N:20]=[CH:19][C:10]1=2
Reactant: c1ccc(C2Nc3ccncc3NC2c2ccccc2)cc1
Reactant: O=CO
Agent: C=O
Agent: CCN1c2ccncc2N(CC)C2CCCCC21
Agent: CN1CCN(C)c2cnccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCCC(C)C
Product: CN1c2cnccc2NC(c2ccccc2)C1c1ccccc1
Temperature: 120 °C

Procedure:
In a 100 ml round-bottomed flask, 0.600 g (2.08 mmol) of 31 were dissolved in 15.5 ml (417.6 mmol, ρ=1.22 g/ml) of formic acid while cooling in ice and 5.1 ml of formaldehyde solution (183.6 mmol, ρ=1.22 g/ml, <37% in water) were added. The ice bath was subsequently removed and the mixture was heated at an oil bath temperature of 120° C. for 48 hours. After cooling to 0° C., 50% strength NaOH was added while cooling in ice until the pH of the mother liquor had risen to 12. The mixture was subsequently extracted three times with 50 ml of DCM and the combined organic phases were dried over Na2SO4. After distilling off the solvent on a rotary evaporator, the crude product was purified by flash chromatography on silica gel (CHCl3/isohexane/NEt3, 10:2:1). This gave 0.564 g (1.87 mmol, 90%) of a yellow solid. Rf=0.40 (CHCl3/isohexane/NEt3, 10:2:1). 1H NMR: (400 MHz, CDCl3): δ=2.85 (s, 3H, CH3), 4.42 (s, 1H, N—H), 4.44 (d, 3J=3.6 Hz, 1H, H-3), 4.95 (d, 3J=3.6 Hz, 1H, H-2), 6.50 (d, 3J=5.2 Hz, 1H, H-8), 6.64 (dd, 4J=2.8 Hz, 3J=9.2 Hz, 2H, 2,6-phenyl-H), 6.90 (m, 2H, 2,6-phenyl-H) 7.05 (m, 2H, phenyl-H), 7.16 (m, 4H, phenyl-H), 7.82 (s, 1H, H-5), 7.84 (d, 3J=5.2 Hz ppm. 13C NMR (75 MHz, CDCl3): δ=37.2 (CH3), 57.8 (C-3), 67.9 (C-2), 107.6 (C-8), 127.4-128.5 (phenyl-C), 131.3 (C-5), 131.6 (Cq, C-4a) 137.4, 138.8 (Cq, phenyl-C), 139.9 (C-7, C-8a) ppm. MS (EI): m/e (%) 302 (22), 301 (M+, 100), 300 (5), 286 (5), 224 (10), 222 (4), 211 (13), 210 (87), 209 (3), 208 (6), 195 (11), 181 (6), 179 (3), 178 (3), 178 (3), 150 (7), 132 (3), 127 (3), 120 (3), 104 (4); 92 (3), 91 (31), 85 (4), 83 (6), 78 (4), 77 (5); IR (neat): ν=3200 (w), 3158 (w), 3029 (w), 2948 (w), 2881 (w), 2824 (w), 1578 (s), 1516 (vs), 1491 (m), 1452 (m), 1421 (m), 1374 (w), 1353 (w), 1326 (w), 1294 (w), 1256 (m), 1235 (m), 1199 (w), 1157 (m), 1131 (m), 1103 (w), 1073 (m), 1054 (m), 1031 (m), 1013 (m), 969 (w), 922 (w), 842 (w), 810 (s), 766 (s), 755 (m), 733 (m), 641 (vs) cm−1. HRMS (EI): calculated for C20H19N3 301.1574 [M+], found: 301.1559.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:7][CH2:8][CH2:9][C:10]1[S:14][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:12][C:11]=1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[S:31][C:32]2[C:37]([N:38]=1)=[CH:36][CH:35]=[CH:34][N:33]=2)=[O:22].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[C:15]1([C:13]2[S:14][C:10]([CH2:9][CH2:8][CH2:7][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:11]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[S:31][C:32]4[C:37]([N:38]=3)=[CH:36][CH:35]=[CH:34][N:33]=4)=[O:22])[N:12]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=CCCc1sc(-c2ccccc2)nc1C(=O)Nc1ccccc1-c1nc2cccnc2s1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(Nc1ccccc1-c1nc2cccnc2s1)c1nc(-c2ccccc2)sc1CCCN1CCCC1
Reaction time: 1 h
Yield: 31.2 %

Procedure:
Pyrrolidine (88 μL, 1.06 mmol) was added to a solution of 5-(3-oxopropyl)-2-phenyl-N-(2-(thiazolo[5,4-b]pyridin-2-yl)phenyl)thiazole-4-carboxamide (250 mg, 0.53 mmol) and AcOH (127 mg, 2.1 mmol) in dichloroethane (DCE) (10 mL). The reaction mixture was stirred for 1 h. Sodium triacetoxyborohydride (449 mg, 2.1 mmol) was added and stirring continued for 16 h. The reaction mixture was poured into sat aq NaHCO3 and extracted with DCM. The combined organics were washed with brine, dried (MgSO4), and concentrated. The crude product was purified by MPLC eluting with CH2Cl2/MeOH+1% TEA (0-10% gradient) to give the title compound (87 mg, 31% yield). MS Calcd for C29H27N5OS2: 525.17. Found (M+H)+ m/z=526.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16](=[S:20])[C:17]([NH2:19])=[O:18]>O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:1][O:2][C:3]1[C:4]2[N:15]=[C:16]([C:17]([NH2:19])=[O:18])[S:20][C:5]=2[C:6]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCOCC2)cc1NC(=S)C(N)=O
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [K+]
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(C(N)=O)nc12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A suspension of 220 mg (0.75 mmol) 2-(2-methoxy-5-morpholin-4-yl-phenylamino)-2-thioxo-acetamide in 2.88 ml 1N aqueous sodiumhydroxde was added to a solution of 813 mg (2.47 mmol) potassium ferricyanide in 2 ml water. The mixture was stirred at 50° C. for 30 minutes and then at room temperature overnight. The precipitate was separated by filtration, dissolved in dichloromethane and purified by column chromatography on silicagel with ethyl acetate/hexane 1/1. 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid amide, 32 mg (15%), was obtained as yellow crystals with mp.: 228-230° C., MS m/e (%): 294 (M+H+, 100).
Reaction SMILES: C([O-])([O-])=O.[K+:5].[K+].[CH2:7]([N:14]1[C:21]2[CH:20]=[C:19]([C:22]([OH:24])=[O:23])[NH:18][C:17]=2[CH:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.CO>[K+:5].[CH2:7]([N:14]1[C:21]2[CH:20]=[C:19]([C:22]([O-:24])=[O:23])[NH:18][C:17]=2[CH:16]=[CH:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1cc2c(ccn2Cc2ccccc2)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C([O-])c1cc2c(ccn2Cc2ccccc2)[nH]1
Reaction time: 0.58 h
Yield: 196.5 %

Procedure:
To a suspension of K2CO3 (24 mg, 0.17 mmol) in H2O (0.2 mL) and MeOH (1 mL) was added a solution of 4-benzyl-1,4-dihydropyrrolo[3,2-b]pyrrole-2-carboxylic acid 13 (82 mg, 0.34 mmol) in MeOH (2 mL). The solution was stirred for 35 min and then concentrated in vacuo to give potassium 4-benzyl-1,4-dihydro-pyrrolo[3,2-b]pyrrole-2-carboxylate 13a as a grey solid (93 mg, 98%). 1H NMR (400 MHz, (CD3)2SO) δ (ppm) 9.61 (s, 1H) 7.27-7.33 (m, 2H) 7.19-7.26 (m, 3H) 6.74 (d, J=2.9 Hz, 1H) 5.90 (s, 1H) 5.73 (dd, J=2.9, 0.8 Hz, 1H) 5.04 (s, 2H).
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([O-:12])=O)=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Na+].[CH3:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][C:25]([F:31])=[C:26]([F:30])[CH:27]=2)[NH:22]1>>[F:30][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[F:31])[N:22]([C:10](=[O:12])[CH2:9][C:5]1[NH:6][C:7](=[O:8])[C:2]([F:1])=[C:3]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:4]=1)[CH:21]([CH3:20])[CH2:29]2
Reactant: CC1Cc2cc(F)c(F)cc2N1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Agent: [Na+]
Product: CC1Cc2cc(F)c(F)cc2N1C(=O)Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Yield: 33.4 %

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 131 mg of sodium (5-fluoro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate obtained in step 2a of example 6a and 93 mg of (+)-2-methyl-5,6-difluoro-2,3-dihydro-1H-indole (reference example 3a). After silica column purification: eluent 98/02 dichloromethane/methanol, 64 mg of 2-[2-((−)-5,6-difluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-5-fluoro-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: COC([CH:5]1[C:11](=O)[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[S:8][C:7]2[CH:17]=[CH:18][C:19]([CH:21]([CH3:26])[C:22]([O:24]C)=[O:23])=[CH:20][C:6]1=2)=O.C(O)(=O)C.Cl.[OH2:32]>>[O:32]=[C:5]1[CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[S:8][C:7]2[CH:17]=[CH:18][C:19]([CH:21]([CH3:26])[C:22]([OH:24])=[O:23])=[CH:20][C:6]1=2
Reactant: COC(=O)C(C)c1ccc2c(c1)C(C(=O)OC)C(=O)c1ccccc1S2
Reactant: O
Agent: Cl
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1ccccc1S2

Procedure:
Methyl 2-(10,11-dihydro-1i-methoxycarbonyl-10-oxodibenzo[b,f]thiepin-2-yl)propionate (prepared in Example 22, 18 mg, 0.040 mmol.), acetic acid (0.3 mL) and 6N hydrochloric acid (0.3 mL) were mixed, and the mixture was heated for 2 hours under reflux. To the reaction mixture was added water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate portion was washed successively with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The dried ethyl acetate portion was placed under reduced pressure to distill the solvent off. The residue was dissolved in toluene and concentrated under reduced pressure to give 14 mg of the desired compound as a white crystalline product.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(OC(=O)C)(=O)C.C(NC1C=CC=CC=1)(=O)C.[N+:27]([O-])([OH:29])=[O:28].OS(O)(=O)=O>>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([N+:27]([O-:29])=[O:28])[C:3]=1[NH2:4]
Reactant: Nc1ccc(F)cc1F
Reactant: O=[N+]([O-])O
Agent: CC(=O)Nc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: Nc1c(F)cc(F)cc1[N+](=O)[O-]

Procedure:
Thus WO 96/02493, starting from 2,4-difluoroaniline, discloses a synthesis proceeding via five stages. 2,4-Difluoroaniline is first reacted with acetic anhydride, the resulting acetanilide is nitrated by means of HNO3 /H2SO4, the acetyl radical is removed and 2,4-difluoro-6-nitroaniline is obtained. By reaction of the 2,4-difluoro-6-nitroaniline with sodium nitrite, the amino group can be removed and 3,5-difluoronitrobenzene is obtained, which can be converted into 3,5-difluoroaniline by reduction.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](O)=[O:28].Cl.[N:35]1[CH:40]=[CH:39][C:38]([C:41]2([NH2:44])[CH2:43][CH2:42]2)=[CH:37][N:36]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:30]=[C:26]([C:27](=[O:28])[NH:44][C:41]2([C:38]3[CH:39]=[CH:40][N:35]=[N:36][CH:37]=3)[CH2:43][CH2:42]2)[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[CH3:33]
Reactant: NC1(c2ccnnc2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccnnc5)CC4)c(OC)cc3C)c(F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.080 g, 0.177 mmol, 1.0 eq), 1-(pyridazin-4-yl)cyclopropanamine HCl (0.024 g, 0.177 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.090 g, 0.89 mmol, 5.0 eq) and BOP reagent (0.117 g, 0.264 mmol, 1.5 eq). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 4% MeOH/CHCl3 as eluent. Yield: 0.060 g (60.0%). 1H NMR (400 MHz, CD3OD): δ 9.08 (m, 1H), 9.05 (d, J=1.0, 5.8 Hz, 1H), 7.97-7.93 (m, 2H), 7.72 (s., 1H), 7.54 (m, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.31-7.25 (m, 3H), 7.19 (s, 1H), 4.10 (s, 3H), 2.95 (s, 3H), 2.30 (s, 3H), 1.63 (s, 4H). 19F NMR (376.57 MHz, CD3OD): δ−112.33, −122.75. LCMS: (ES+) m/z=569.2 (M+H)+
Reaction SMILES: [CH2:1]([N:8]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20]C=1)=[O:15])[CH2:9][CH2:10][C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[Li+].[Cl-].[CH2:40]([C@@H:47]1[CH2:51][O:50][C:49](=[O:52])[NH:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[C:17]1([O:16][C:14](=[O:15])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10][C:11]([N:48]2[C@H:47]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:51][O:50][C:49]2=[O:52])=[O:13])[CH:18]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: O=C(O)CCN(Cc1ccccc1)C(=O)OCc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)N(CCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1)Cc1ccccc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-{benzyl[(benzyloxy)cabonyl]amino}propanoic acid (13.80 g, 44.04 mmol) and triethylamine (18.5 mL, 132.1 mmol) in anhydrous THF (220 mL) at −25° C. was slowly added pivaloyl chloride (6.03 mL, 48.44 mmol) to immediately form a white precipitate. The reaction mixture was stirred at −20° C. for 1 h, prior to the sequential addition of LiCl and (R)-(+)-4-benzyl-2-oxazolidinone. After stirring the reaction mixture at rt for 16 h, the reaction was quenched with saturated aqueous NaHCO3 (80 mL) and water (80 mL). The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by Combiflash (20-40% EtOAc/hexane) to give benzyl-{3-[(4R)-benzyl-2-oxo-1,3-oxazolidin-3-yl)-3-oxo-propyl]-carbamic acid phenyl ester as a colorless semi-solid (17.00 g, 82% in yield). MS (ESI): 473.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.Br[CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:23]([O:22][C:20]([CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:6][CH:7]=1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(OCC(=O)OCc2ccccc2)cc1

Procedure:
t-Butyl [2-(4-hydroxyphenyl)ethyl]carbamate, benzyl bromoacetate and potassium carbonate were heated in acetone. t-Butyl [p-[[(benzyloxy)-carbonyl]methoxy]phenethyl]carbamate, MS: 385 (0.5, M), was obtained.