Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[N:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[CH:22]=[CH:21][C:20]=3[CH3:31])[C:9]=2[C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH3:3]>CC(O)C>[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[N:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[CH:22]=[CH:21][C:20]=3[CH3:31])[C:9]=2[C:10]([NH2:1])=[N:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: N
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4cn(C)nn4)ccc3C)csc12
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4cn(C)nn4)ccc3C)csc12
Temperature: 140 °C

Procedure:
Ammonia gas was bubbled into a solution of 4-chloro-3-[2-methyl-5-(1-methyl-1H-[1,2,3]triazol-4-yl)-phenoxy-methyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.17 g, 0.38 mmol) (from Example 22 supra) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140° C. for 2 hours. The reaction mixture was concentrated. The residue washed with hot methanol, filtered and dried to give 4-amino-3-[2-methyl-5-(1-methyl-1H-[1,2,3]triazol-4-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.10 g, 63%).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([P:18]([NH:24][CH2:25][CH2:26][CH3:27])([NH:20][CH2:21][CH2:22][CH3:23])=[O:19])[C:13]1=[O:28])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([P:18]([NH:24][CH2:25][CH2:26][CH3:27])([NH:20][CH2:21][CH2:22][CH3:23])=[O:19])[C:13]1=[O:28]
Reactant: CCCNP(=O)(NCCC)N1CCC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CCCNP(=O)(NCCC)N1CCC[C@H](N)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Palladium black (50 mg) was added to a solution of (3S)-3-benzyloxycarbonylamino-1-bis(n-propylamino)phosphinyl-2-piperidone (500.0 mg, 1.2182 mmol) in methanol (5 mL), and the resulting mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C:3]([N:5]1[CH2:12][C:11]2[C:10]([NH:13][C:14](=[O:22])[C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:9][N:8](C(OCC)=O)[C:7]=2[C:6]1([CH3:29])[CH3:28])=[O:4].C(Cl)Cl.CO>CO>[CH3:1][C:2]([CH3:31])([CH3:30])[C:3]([N:5]1[CH2:12][C:11]2[C:10]([NH:13][C:14](=[O:22])[C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)=[N:9][NH:8][C:7]=2[C:6]1([CH3:29])[CH3:28])=[O:4]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccc(F)cc2)c2c1C(C)(C)N(C(=O)C(C)(C)C)C2
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)C(=O)N1Cc2c(NC(=O)c3ccc(F)cc3)n[nH]c2C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Ethyl 5-(2,2-dimethylpropanoyl)-3-[(4-fluorobenzoyl)amino]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate (2.0 g, 4.64 mmol) was dissolved in methanol (60 ml), treated with TEA (6.45 ml, 46.4 mmol, 10 eq) and stirred overnight at room temperature. (TLC: CH2Cl2/MeOH 95/5). After evaporation, the solid was treated with diethyl ether/hexane and filtered to afford 1.43 g of the title compound in 86% yield.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:31]=[CH:30][C:13]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[N:25]([CH:26]([CH3:28])[CH3:27])[C:24]([CH3:29])=[N:23][CH:22]=4)[CH:18]=[CH:17][N:16]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.Cl>C(O)(C)C>[N:7]1([C:10]2[CH:31]=[CH:30][C:13]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[N:25]([CH:26]([CH3:28])[CH3:27])[C:24]([CH3:29])=[N:23][CH:22]=4)[CH:18]=[CH:17][N:16]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1
Reactant: CC(=O)N1CCN(c2ccc(Nc3nccc(-c4cnc(C)n4C(C)C)n3)cc2)CC1
Agent: Cl
Solvent: CC(C)O
Product: Cc1ncc(-c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)n1C(C)C

Procedure:
2-[4-(4-Acetylpiperazin-1-yl)anilino]-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidine (Example 18; 1.3 g) was stirred and heated in isopropanol (15 ml) and 33% hydrochloric acid (1.5 ml) at 90° C. for 4.5 hours. The reaction was evaporated under reduced pressure and then basified with 7N ammonia in MeOH and re-evaporated. Toluene was added and the mixture was re-evaporated (3 times). The residue was purified by chromatography on neutral alumina, activity II eluting with MeOH:DCM (5:95) to give the title compound as a yellow gum. (330 mg 28%). NMR: 1.40 (d, 6H), 2.46 (s, 3H), 2.82 (m, 4H), 2.96 (m, 4H), 5.69 (septuplet, 1H), 6.85 (d, 2H), 6.93 (d, 1H), 7.18 (s, 1H), 7.42 (d, 2H), 8.30 (d, 1H), 9.11 (s, 1H); m/z 378.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].O1CCOCC1>C(Cl)Cl>[ClH:23].[ClH:23].[N:11]1([C:14]2[C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2noc3ccncc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1cc2onc(N3CCNCC3)c2cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Isoxazolo[4,5-c]pyridin-3-yl-piperazine-1-carboxylic acid tert-butyl ester (960 mg, 3.1 mmol) was dissolved in CH2Cl2 (2 ml) and 4 N HCl in dioxane (15.7 ml, 63 mmol) was added. The resulting mixture was stirred 16 h at r.t. After dilution with iPr2O the product was collected by filtration and washed with one portion of iPr2O before drying it under high vacuum at 50° C. to obtain 850 mg (97%) as a pink solid. m/z=205.2 ([M+H]+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:25])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)[N:10]=2)[N:7]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].CC(O)C>O>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:25])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)[N:10]=2)[N:7]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1ccc(-c2nc3ccc(Cl)nn3c2C)cc1NC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(-c2nc3ccc(-c4ccccc4F)nn3c2C)cc1NC(=O)C(C)(C)C
Temperature: 80 °C
Yield: 62.6 %

Procedure:
To a mixture of N-(5-(6-chloro-3-methylimidazo[1,2-b]pyridazin-2-yl)-2-methylphenyl)pivalamide (0.100 g, 0.280 mmol), 4-fluorophenylboronic acid (0.420 mmol), Na2CO3 (0.840 mmol), 2-propanol (9 mL) and water (3 mL) that has been degassed with N2 (5 minutes) is added PdCl2(PPh3)2(0.0280). The mixture is heated at 80° C. for 12 hours, diluted with sat. aqueous NaHCO3 (50 mL) and extracted with EtOAc (3×25 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography using a gradient of hexanes to EtOAc to afford the title compound (0.073 g, 62%) as a yellow solid: Rf 0.29 (1:1 EtOAc:hexanes); LCMS (m/z)=417.5 [M+H]+, tR=2.71 min. (compound same as Example 312)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:29]5[CH:30]=[N:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)sc2CCO3)cn1
Yield: 17 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 6-methoxypyridin-3-ylboronic acid were reacted to give 305 (0.027 g, 17%). 1H NMR (400 MHz, DMSO) δ 8.62 (d, J=2.3, 1H), 8.48 (d, J=2.0, 1H), 8.11 (s, 1H), 7.99 (dd, J=8.6, 2.5, 1H), 7.60 (dd, J=8.4, 2.3, 1H), 7.18 (d, J=8.4, 1H), 6.96 (d, J=8.6, 1H), 5.77 (dt, J=13.3, 6.8, 1H), 4.42 (t, J=4.9, 2H), 3.91 (s, 3H), 3.48 (t, J=4.8, 2H), 1.57 (d, J=6.6, 6H). MS (ESI(+)): m/z 420.1 (M+H)
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]#[N:26])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.CO.C(Cl)Cl>[ClH:18].[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH:12]2[CH2:13][CH2:14][N:15]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]#[N:26])[CH:20]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)C2CCNCC2)CC1
Reactant: N#Cc1cc(Cl)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)N1CCN(C(=O)C2CCN(c3ccnc(C#N)c3)CC2)CC1
Reaction time: 2 h
Yield: 63.9 %

Procedure:
1-Isopropyl-4-(pipeddine-4-carbonyl)-piperazine (D1)(0.116 g), 4-chloro-2-cyanopyridine (T. Sakamoto, S-I. Kaneda, S. Nishimura and H. Yamanaka, Chem. Pharm. Bull., 1985, 33(2), 565-571)(0.2 g) and anhydrous potassium carbonate (0.347 g) were heated in dry DMSO at 150° C. with stirring, under argon, for 2 h. The cooled mixture was diluted with methanol and applied to an SCX resin column. The column was eluted initially with methanol and then with methanolic ammonia (2M). The ammoniacal eluates were concentrated and the resulting gum was further purified by silica gel chromatography eluting with 0-10% methanolic ammonia (2M) in DCM. The free-base thus obtained was dissolved in DCM (5 ml) and treated with ethereal HCl (1.0M, 5 ml). The resulting suspension was evaporated to dryness by blowing down with a gentle stream of argon, to give the title compound (E98) as an off-white solid (0.117 g). 1H NMR δ [DMSO-d6]: 1.29 (6H, d, J=7 Hz), 1.48-1.63 (2H, m), 1.75 (2H, m), 2.89 (1H, br. m), 3.02-3.14 (5H, m), 3.38 (2H, m), 3.47 (1H, m), 3.65 (1H, m), 4.11 (2H, br. m), 4.24 (1H, br. d, J≈14 Hz), 4.48 (1H, br. d, J≈14 Hz), 7.15 (1H, dd, J=7,3 Hz), 7.65(1H, d, J=3 Hz), 8.26 (1H, d, J=7 Hz), 11.10 (1H, br.); LCMS electrospray (+ve) 342 (MH+).
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-:2].[Na+:5].[Na+].[C:7](=[O:10])([OH:9])[O-:8].[Na+].C(=O)=O>>[C:1](=[O:2])([OH:4])[O-:3].[Na+:5].[C:7](=[O:8])([OH:10])[OH:9]
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Product: O=C(O)O

Procedure:
In this process, as can be seen from reaction formula 4, some sodium carbonate is consumed by reacting with the PCB to form NaCl. Moreover, as shown by reaction formula 5, some sodium carbonate is converted into sodium bicarbonate by reaction with the resulting carbon dioxide. Furthermore, as shown by reaction formula 6, the carbon dioxide existing in excess is used to form an aqueous solution of sodium bicarbonate and carbonic acid. Thus, the sodium carbonate particles were exhausted and, therefore, the PCB decomposition reaction is retarded to an extreme degree.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.Cl.[F:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CS(C)=O.CO>[F:26][CH:27]1[CH2:31][CH2:30][N:29]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:28]1
Reactant: FC1CCNC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCC(F)C3)n2n1
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 86 mg, 0.25 mmol), 3-fluoropyrrolidine hydrochloride (63 mg, 0.75 mmol), and N,N-diisopropylethylamine (116 mg, 0.90 mmol) in DMF (1.0 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (30-30% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (73.5 mg, 74%). 1H NMR (DMSO-d6) δ: 10.82 (s, 1H), 7.98 (d, J=8.6 Hz, 2H), 7.61 (d, J=8.3 Hz, 2H), 6.89 (s, 1H), 6.11 (s, 1H), 5.50 (d, J=52.0 Hz, 1H), 4.05-4.45 (m, 3H), 3.86-3.96 (m, 1H), 2.35 (s, 3H), 2.24-2.33 (m, 1H), 2.11-2.24 (m, 1H), 1.45 (s, 6H); ESI-MS: m/z 398.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](=[O:18])[NH:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1CCN2C(=NCCC2)CC1.[CH3:63][C:64]1[NH:65][C:66]2[C:71]([CH:72]=1)=[CH:70][C:69](O)=[CH:68][CH:67]=2>>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([O:18][C:69]3[CH:70]=[C:71]4[C:66](=[CH:67][CH:68]=3)[NH:65][C:64]([CH3:63])=[CH:72]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(nc[nH]c2=O)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc2cc(Oc3ncnc4c3CCN(C(=O)OC(C)(C)C)C4)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 4-oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester, Example 31-A, (300 mg, 1.2 mmol) in I (5 mL) is added PyBOP (800 mg, 1.55 mmol) and DBU (0.2 mL, 1.43 mmol). After 20 min 2-methyl-1H-indol-5-ol (211 mg, 1.43 mmol) is added. The mixture is then stirred at room temperature for 16 h. At that point the reaction is concentrated under reduced pressure and the residue is dissolved in EtOAc and washed by water and brine. The organic layer is dried over sodium sulfate, concentrated under reduced pressure. The residue is purified by FCC (EtOAc/heptane from 0% to 40%) to give the title compound. MS (ESI) m/z 381.0 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:7]=1[C:8]#[N:9]>CCO.[Ni]>[NH2:9][CH2:8][C:7]1[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:6]=1[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc(O)ccc1-c1ccco1
Agent: [Ni]
Solvent: CCO
Product: NCc1cc(O)ccc1-c1ccco1
Reaction time: 8 h

Procedure:
2-Furan-2-yl-5-hydroxy-benzonitrile (100 mg, 0.54 mmol) is dissolved in EtOH (10 mL) to which Raney Ni (excess) is added. The mixture is subjected to hydrogenation under H2 (50 psi) for overnight. The mixture is then filtered and solvent removed to afford the crude product, which is carried over to the next step without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9]Br.[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[OH:20])[CH:15]=[O:16]>CC(C)=O>[O:20]1[C:19]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=2[O:11][CH2:9][CH2:8]1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc2c(c1)OCCO2
Temperature: 55 °C
Reaction time: 12 h
Yield: 73.3 %

Procedure:
A 2000 L reactor was charged with acetone (404.5 kg), followed by potassium carbonate (256 kg, 1852 mol) and 1,2-dibromoethane (241.5 kg, 1298 mol). The mixture was heated at reflux. A 500 L reactor was charged with acetone (606 kg) and 3,4-dihydroxybenzaldehyde (128 kg, 926 mol). The contents of the 500 L reactor were added to the 2000 L reactor at a rate of 150-180 kg/h while the reaction temperature was maintained at 50-60° C. The reaction mixture was stirred at 54-60° C. for 12 h, was cooled to 20° C. and was filtered through a 500 L Nutsche filter. The filter cake was washed with acetone (2×202 kg). The filtrate and acetone washes were combined in a 2000 L reactor and the resultant solution was concentrated to dryness under reduced pressure at a temperature<40° C. To the residue was added ethyl acetate (683 kg) and the resultant solution was washed with a 5% by weight aqueous solution of potassium carbonate (256 kg). The mixture was stirred for 0.5 h, allowed to settle for 0.5 h and the aqueous phase was removed. This washing procedure was repeated three times in total. The organic phase was temporarily set aside into drums. A 2000 L reactor was charged with the combined aqueous washes, followed by ethyl acetate (113.9 kg). The mixture was stirred for 0.5 h, allowed to settle for 0.5 h and the aqueous phase was removed. The organic phase from the drums was added to the reactor followed by a 28% by weight aqueous solution of sodium chloride (192 kg). The mixture was stirred for 0.5 h, allowed to settle for 0.5 h and the aqueous phase was removed. The organic phase was concentrated under reduced pressure at a temperature<45° C. until the mixture's ethyl acetate content was below 10% (as determined by gas chromatography). Petroleum ether (268.8 kg) was added to the residue at a rate of 80-90 kg/h while the mixture was maintained at a temperature of 35-45° C. The mixture was cooled to 5° C. over 3 h and held at this temperature for a further 1 h, during which time a precipitate was deposited. The resultant slurry was filtered through a centrifugal filter and dried to afford 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (111.4 kg, 73%) as an off-white solid: purity (HPLC-UV at 230 nm) 99.3%.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH:35]([CH3:37])[CH3:36]>CN(C)C=O>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH:35]([CH3:37])[CH3:36])[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCN(C4CCC4)CC3)ccc21
Yield: 34 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), sodium hydride and 2-bromopropane in N,N-dimethylformamide, to give the desired product as a colorless foam (34%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2Br)[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1B(O)O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(COC)OC>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:33]2[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:32]=2[O:31][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=1)[CH3:2]
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Reactant: CCOC(=O)c1cccc(C2=C(Br)CCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)c1cccc(C2=C(c3cc(Cl)ccc3OCc3ccccc3)CCC2)c1

Procedure:
3-(2-Bromocyclopent-1-enyl)-benzoic acid ethyl ester (0.148 g, 0.0005 mol), Pd(0)[PPh3]4 (30 mg), potassium carbonate (0.2 g) and (2-benzyloxy-5-chlorophenyl) boronic acid (150 mg, 0.0005 mol) in dimethoxyethane (5 mL) were refluxed for 17 h under nitrogen. The reaction mixture was then filtered through Kieselghur and evaporated down to an oil. Purification was carried out on a Water's separation pack (10 g) with dichloromethane/isohexane giving the product (85 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:44])([C:20]3[N:21]=[CH:22][N:23](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:24]=3)[CH:17]([CH3:19])[CH3:18])[CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].[Cl-].[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CO>[CH2:1]([NH:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:44])([C:20]3[N:21]=[CH:22][NH:23][CH:24]=3)[CH:17]([CH3:19])[CH3:18])[CH:12]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCNC(=O)c1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A mixture of N-ethyl-6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthamide (11.5 g) and pyridinium chloride (4.62 g) in methanol (60 mL) was stirred at 60° C. for 2 h. The mixture was neutralized with sodium bicarbonate solution and concentrated. The residue was dissolved in ethanol and insoluble material was filtered off. The filtrate was concentrated and purified by column chromatography (eluent; dichloromethane:methanol=10:1→7:1) to give the titled compound (5.75 g) as a colorless powder.
Reaction SMILES: O=O.[OH:3][CH2:4][CH:5]=[C:6]([CH3:17])[CH:7]=[CH:8][CH:9]=[C:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].CC1(C)CCCC(C)(C)[NH+]1[O-].[Cl-].[Na+]>CN(C)C=O.[Cu]Cl>[CH3:16][C:10](=[CH:9][CH:8]=[CH:7][C:6]([CH3:17])=[CH:5][CH:4]=[O:3])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C)=CC=CC(C)=CCO
Agent: Cl[Cu]
Agent: CC1(C)CCCC(C)(C)[NH+]1[O-]
Agent: O=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)=CC=CC(C)=CC=O
Reaction time: 1 h
Yield: 91.9 %

Procedure:
From 50 to 60 ml of oxygen per minute were passed through a solution of 30.0 g (142.7 millimoles) of ethyl 8-hydroxy-2,6-dimethylocta-2,4,6-trien-1-oate (isomer mixture) and 2.23 g (14.3 millimoles) of 2,2,6,6-tetramethylpiperidine 1-oxide in 75 ml of N,N-dimethylformamide, after the addition of 1.42 g (14.3 millimoles) of copper(I) chloride, the temperature being kept at from 20° to 35° C. with the aid of an ice bath. After 1 hour, the mixture was poured onto 150 ml of aqueous sodium chloride solution and extracted with methyl tert-butyl ether. The organic phase was first washed with a solution of sodium iodide in 5% strength hydrochloric acid, shaken with aqueous sodium thiosulfate solution, washed with water and then dried over sodium sulfate, after which the solvent was removed under reduced pressure. 27.3 g (92% yield) of ethyl 2,6-dimethyl-8-oxoocta-2,4,6-trien-1-oate were obtained.
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].C([Li])(C)(C)C.CN([CH:21]=[O:22])C.Cl>C1COCC1>[CH2:1]([C:3]1([C:8]2[S:9][C:10]([CH:21]=[O:22])=[CH:11][CH:12]=2)[O:4][CH2:5][CH2:6][O:7]1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCC1(c2cccs2)OCCO1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCC1(c2ccc(C=O)s2)OCCO1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
15 g (81.4 mmol) of 2-ethyl-2-2-thienyl-[1,3]dioxolane are dissolved in 300 mL of anhydrous THF and the mixture is then cooled to −78° C. 53 mL (89 mmol) of 1.7 M tert-butyllithium solution are then added, after which the reaction medium is stirred for 1 hour. 10 mL (120 mmol) of anhydrous DMF are then added and the medium is stirred for 1 hour. The reaction medium is treated at −78° C. with 1N hydrochloric acid solution and is then extracted with ethyl acetate and the organic phases are combined, dried and concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica. A yellow oil is obtained (m=19 g; Y=100%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.I[CH:21]([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:22][CH:21]([CH3:23])[CH:14]([C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CC(C)I
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)C(c1nc(N2CCOCC2)cc(=O)[nH]1)C(C)C

Procedure:
The product is prepared according to the procedure described in example 67, using 600 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 1 and 0.29 ml of 2-iodopropane in place of the methyl iodide, and replacing the potassium carbonate with cesium carbonate. After purification by silica column chromatography, eluent: 90/05/05 CH2Cl2/CH3CN/MeOH, 20 mg of ethyl 3-methyl-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]butanoate are obtained in the form of a white solid, the characteristics of which are the following: