Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[CH2:18]=O>C(O)C>[C:2]1([NH:1][CH2:18][N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[S:10][C:9]2=[S:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: Nc1ccccc1
Reactant: Sc1nc2ccccc2s1
Solvent: CCO
Product: S=c1sc2ccccc2n1CNc1ccccc1
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
With stirring, 18.63 g (0.2 mole) of aniline are added to a suspension of 33.45 g (0.2 mole) of 2-mercaptobenzothiazole in 120 ml of ethanol, the temperature rising to 30° C. Then 16.4 g (0.2 mole) of 37% aqueous formaldehyde solution are added and stirring is continued for 30 minutes. The precipitate is isolated by filtration and washed with cold ethanol and hexane, affording 47 g of 3-(phenylaminomethyl)benzothiazoline-2-thione which melts at 102°-103° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].[Cl:21][C:22]([C:28]1[CH:29]=[CH:30][C:31]([O:38][CH3:39])=[C:32]([S:34](Cl)(=[O:36])=[O:35])[CH:33]=1)([Cl:27])[C:23]([F:26])([F:25])[F:24]>C(Cl)Cl.N1C=CC=CC=1>[Cl:21][C:22]([C:28]1[CH:29]=[CH:30][C:31]([O:38][CH3:39])=[C:32]([S:34]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH:13]=2)(=[O:11])=[O:10])(=[O:36])=[O:35])[CH:33]=1)([Cl:27])[C:23]([F:26])([F:25])[F:24]
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Reactant: COc1ccc(C(Cl)(Cl)C(F)(F)F)cc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(Cl)(Cl)C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-aminophenyl)-amide (1 mmol, prepared as in Example 1) in DCM (2 mL) and pyridine (2 mL), 5-(1,1-dichloro-2,2,2-trifluoroethyl)-2-methoxybenzenesulfonyl chloride (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (20 mL). The organic phase was washed with 10% aqueous HCl (20 mL), water (20 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to afford 374 mg of benzo[b]thiophene-2-sulfonic acid [2-(5-(1,1-dichloro-2,2,2-trifluoroethyl)-2-methoxy-benzenesulfonylamino)phenyl]-amide. LC: Tr 1.40 min; MS: 625.8 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:10][C:11](Cl)=[O:12].[OH:14][CH:15]([CH:18]1[CH2:23][CH2:22][N:21]([O:24][CH3:25])[CH2:20][CH2:19]1)[C:16]#[N:17].CCN(CC)CC>C1COCC1>[C:16]([CH:15]([O:14][C:11](=[O:12])[CH2:10][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=1[CH3:9])[CH:18]1[CH2:19][CH2:20][N:21]([O:24][CH3:25])[CH2:22][CH2:23]1)#[N:17]
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Reactant: CON1CCC(C(O)C#N)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON1CCC(C(C#N)OC(=O)Cc2c(C)cc(C)cc2C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(2,4,6-Trimethyl-phenyl)-acetyl chloride (588 mg, 3 mmol) was added slowly to a mixture of hydroxy-(1-methoxy-piperidin-4-yl)-acetonitrile (390 mg, 2.3 mmol) and Et3N (505 mg, 5 mmol) in THF (10 ml) at 0° C. After the addition was completed, the mixture was stirred at room temperature for 16 h. Then, the mixture was concentrated under vacuum to dryness, the residue was purified by column chromatography on silica.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.Cl.C([O-])(O)=O.[Na+]>ClCCl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:10]
Reactant: OCCCCCCCCO
Reactant: C1=COCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: OCCCCCCCCOC1CCCCO1
Yield: 99.7 %

Procedure:
1,8-Octanediol (16.8 g) (115 mmol) and 4.83 g of dihydropyran (57.5 mmol) in 1400 ml of dichloromethane containing 5 drops of concentrated HCl were stirred for 2 hours. Then 10 g of NaHCO3 were stirred in and the solution was filtered. Dichloromethane was removed with a rotary evaporator, and the resulting residue was triturated with pentane; the undissolved solid was 1,8-octanediol. The solid was filtered from the pentane solution, and the pentane was removed with a rotary evaporator to give 13.2 g (99.8%) of crude product oil.
Reaction SMILES: [SH:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C[O-].[Na+].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO>[CH2:10]([S:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Sc1nc[nH]n1
Reactant: ClCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(CSc2nc[nH]n2)cc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
A solution of 30 g (0.29 m) 3-mercapto-1,2,4-triazole in 300 ml of dry methanol containing 16.0 g (0.29 m) sodium methoxide is stirred under dry conditions, cooled to 5° C. and benzylchloride 41.3 g (0.32 m) is added dropwise. Stir the mixture at room temperature overnight, reflux 2 hours, cool and evaporate to dryness. The residue is stirred in water and the product is extracted with ethyl acetate. Dry the ethyl acetate layer and evaporate to dryness to give white product. Recrystallize from toluene-hexane, white crystals, 41.4 g (73%), m.p. 79°-80° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[CH3:27])[N:13]=[C:12]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[CH3:27])[N:13]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCN(C(=O)OC(C)(C)C)CC3)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c(C)c1

Procedure:
To a solution of 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.4 mmol) in toluene (3 mL) was added 4-methoxy-2-methyl-benzyl chloride (0.9 mmol) and cyanomethylene-tri-n-butylphosphorane (1 mmol). The mixture was heated at 110° C. for 16 h. After concentration and purification (SiO2, EtOAc/hexanes), 3-(4-chloro-phenyl)-1-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester was obtained (54 mg). The other regioisomer, 3-(4-chloro-phenyl)-2-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester, was also obtained (86 mg). 3-(4-Chloro-phenyl)-1-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (20 mg) was treated with TFA (1 mL) in CH2Cl2 (10 mL) for 4 h. After concentration of the reaction mixture, the title compound was obtained (0.02 g). MS (ESI): exact mass calculated for C22H24ClN3O, 381.16; found, m/z 382.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.37 (m, 2H), 7.34-7.32 (m, 2H), 6.68-6.66 (br m, 1H), 6.54-6.52 (br m, 1H), 6.37 (d, J=8.3 Hz, 1H), 5.21 (s, 2H), 2.81-2.79 (m, 4H), 2.71-2.69 (m, 4H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=2)[CH2:23][CH2:24][O:25][CH2:26][CH2:27][C:28](O)=[O:29])[CH:17]=[N:16]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C(=O)(O)[O-].[Na+].C(OC(C)C)(=O)C>O1CCCC1.C(N(CC)CC)C>[CH:6]1([N:5]([CH2:4][CH:3]([O:12][CH3:13])[O:2][CH3:1])[C:28](=[O:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23][C:22]2[CH:31]=[CH:32][CH:33]=[C:20]([C:18]3[CH:17]=[N:16][N:15]([CH3:14])[CH:19]=3)[CH:21]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(CNC1CCCCC1)OC
Reactant: Cn1cc(-c2cccc(CCOCCC(=O)O)c2)cn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)C
Solvent: C1CCOC1
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cnn(C)c2)c1)C1CCCCC1)OC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of N-(2,2-dimethoxyethyl)cyclohexanamine (21.5 g) in tetrahydrofuran (30 mL) was added to a solution of 3-(3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid in tetrahydrofuran (105 mL) at 20° C. Tetrahydrofuran (15 mL) was added, followed by triethylamine (51.8 mL), followed by a solution of T3P in tetrahydrofuran (121.9 mL of a 1.62M solution). The solution was stirred at 20° C. for 1 h then cooled to 10° C. Pre-chilled (10° C.) 0.5M sodium bicarbonate solution (225 mL) was added, followed by iso-propyl acetate (150 mL). After mixing the layers were separated and the organic layer washed with 20% w/w sodium chloride solution (150 mL), then evaporated to dryness to afford the subtitled compound as a brown oil (48.6 g). MS [M+H-MeOH]+=412.20 (100%) (MultiMode+) [M+H]+=444.20 (MultiMode+) 1H NMR (300 MHz, CDCl3) δ 7.75 (s, 1H), 7.62 (s, 1H), 7.33-7.23 (m, 3H), 7.10-7.03 (m, 1H), 4.61 (t, 0.7H), 4.36 (t, 0.3H), 3.94 (s, 3H), 3.79 (q, 2H), 3.69 (q, 2H), 3.62-3.43 (m, 1.5H), 3.40 (s, 3H), 3.38 (s, 3H), 3.30 (d, 1.5H), 2.89 (q, 2H), 2.69 (quintet, 2H), 1.86-0.99 (m, 10H); approx:2:1 ratio of rotamers
Reaction SMILES: C[C:2]([CH3:5])([O-])[CH3:3].[Na+].[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[OH2:16]>CN(C=O)C>[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[C:2]([CH3:5])[CH2:3][OH:16])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=Cc1ccc(Br)cc1)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of sodium tert-butoxide (10.6 g, 110 mmol) in DMF (60 mL) was added triethyl phosphonoacetate (26.2 g, 110 mmol) under argon atmosphere at −10° C. and the mixture was stirred at the same temperature for 1 hour. 4-bromobenzaldehyde (18.5 g, 100 mmol) was added to the solution at 10° C. or lower, and the mixture was warmed to room temperature, and then stirred for 2 hours. Water was added to the reaction solution after ice-cooling, which was extracted with toluene. The extract was washed with a saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained oily matter was dissolved in toluene (200 mL), dihydrobis(2-methoxyethoxy) sodium aluminate (a 70% toluene solution, 41.5 g, 144 mmol) was added dropwise at −10° C., and then the mixture was stirred at the same temperature for 1 hour. A 10% aqueous potassium sodium tartrate solution was added to separate the organic layer. The organic layer was washed with a 10% aqueous potassium sodium tartrate solution and a saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 20.1 g (yield 88%) of the title compound as an oily matter.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]1[CH:14]=[CH:15][C:16]([C:18](OCC#N)=[O:19])=[CH:17][N:8]1[C:7]2=[O:24])[CH3:3].[N:25]1([CH:30](N)[CH2:31][CH2:32][CH3:33])[CH:29]=[CH:28][N:27]=[CH:26]1.C[N:36](C)C=O>O>[N:25]1([CH2:30][CH2:31][CH2:32][CH2:33][NH:36][C:18]([C:16]2[CH:15]=[CH:14][C:9]3[N:8]([CH:17]=2)[C:7](=[O:24])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([CH:2]([CH3:3])[CH3:1])[CH:5]=2)[N:10]=3)=[O:19])[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: CN(C)C=O
Reactant: CCCC(N)n1ccnc1
Reactant: CC(C)c1ccc2nc3ccc(C(=O)OCC#N)cn3c(=O)c2c1
Solvent: O
Product: CC(C)c1ccc2nc3ccc(C(=O)NCCCCn4ccnc4)cn3c(=O)c2c1
Yield: 85 %

Procedure:
A solution of 1.30 g of cyanomethyl 2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylate and 1.20 g of (1H-imidazol-1-yl)butanamine in 15 ml of dimethylformamide was stirred at a bath temperature of 35° C. for 18 hours. The reaction mixture was diluted with water and the crude precipitate was recrystallized from acetonitrile to give 1.41 g (85%) of N-[4-(1H-imidazol-1-yl)butyl]-2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxamide, mp 165°-167° C.
Reaction SMILES: [N:1]1([C:5]2[S:6][C@H:7]3[O:13][C@@H:12]([CH2:14][OH:15])[C@H:11](C4C=CC=CC=4C([O-])=O)[C@H](C4C=CC=CC=4C([O-])=O)[C@H:8]3[N:9]=2)[CH2:4][CH2:3][CH2:2]1.CCN(S(F)(F)[F:40])CC.CO.[C:45]([O-:48])([O-])=O.[K+].[K+]>C(Cl)Cl.CC(O)=O>[N:1]1([C:5]2[S:6][C@H:7]3[O:13][C@H:12]([CH2:11][F:40])[C@@H:14]([OH:15])[C@H:45]([OH:48])[C@H:8]3[N:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])c1ccccc1[C@@H]1[C@H]2N=C(N3CCC3)S[C@H]2O[C@@H](CO)[C@@H]1c1ccccc1C(=O)[O-]
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: O[C@H]1[C@H](O)[C@@H](CF)O[C@@H]2SC(N3CCC3)=N[C@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of -(3aR,5R,6S,7R,7aR)-2-(azetidin-1-yl)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diyldibenzoate (100 mg, 0.2 mmol) in DCM (10 mL) was treated with DAST (137 mg, 0.8 mmol) for 30 min at −78° C. After stirring overnight at room temperature, the reaction was quenched with satd. aqueous NaHCO3 (10 mL), extracted with DCM (3×10 mL), washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude product as a white syrup (80 mg), which was dissolved into MeOH (5 mL) and treated with K2CO3 (10 mg, 0.07 mmol) for 3 h at room temperature. The reaction mixture was neutralized by AcOH and concentrated. The residue was purified by a silica gel column, eluted with 5%-10% MeOH in DCM to give -(3aR,5S,6S,7R,7aR)-2-(azetidin-1-yl)-5-(fluoromethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol as white solid (10 mg, 17%, two steps). (ES, m/z): [M+H]+ 263.0; 1H NMR (300 MHz, D2O) δ 6.30 (d, J=6.3 Hz, 1H), 4.49-4.69 (dd, J=57, 3.3 Hz, 1H), 4.11-4.15 (m, 1H), 3.93-4.01 (m, 5H), 3.70-3.82 (m, 1H), 3.59-3.69 (m, 1H), 2.24-2.34 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:15]=2[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[C:35]1[NH:39][C:38]2[CH:40]=[C:41](B3OC(C)(C)C(C)(C)O3)[CH:42]=[CH:43][C:37]=2[N:36]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.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:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:41]3[CH:42]=[CH:43][C:37]4[N:36]=[C:35]([CH:31]5[CH2:32][CH2:33][CH2:34][N:30]5[C:28]([O:27][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:29])[NH:39][C:38]=4[CH:40]=3)[CH:20]=[CH:21][C:15]=2[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(Br)cc2[nH]1
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: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(-c3ccc4nc(C5CCCN5C(=O)OC(C)(C)C)[nH]c4c3)cc2[nH]1
Temperature: 110 °C
Yield: 15.1 %

Procedure:
A mixture of 2-(6-bromo-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (64 mg, 0.174 mmol), 2-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (72 mg, 0.174 mmol), tetrakis(triphenylphosphine)palladium (30 mg, 0.026 mmol) and potassium carbonate (48 mg, 0.35 mmol) in 2 ml 1,2-dimethoxyethane and 1 mL water was heated to 110° C. in microwave for 15 minutes. The reaction mixture was cooled and dissolved in ethyl acetate and washed with 5% lithium chloride aqueous solution. The organic layer dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 10% methanol/ethyl acetate) to give 2-[2′-(1-Boc-pyrrolidin-2-yl)-3H,3′H-[5,5]bibenzoimidazolyl-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (15 mg, yield 15%). LCMS-ESI−: calc'd for C32H40N6O4: 572.70; Found: 573.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][N:27]4[S:33]([CH3:32])(=[O:35])=[O:34])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1
Reactant: CS(=O)(=O)Cl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1S(C)(=O)=O
Yield: 58.3 %

Procedure:
Using an analogous procedure to that described for the preparation of Example 22, 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline (150 mg, 0.36 mmol), (prepared as described for the starting material in Example 12), was reacted with methanesulphonyl chloride (33 μl, 0.43 mmol). The product was purified by column chromatography, eluting with methanol/methylene chloride (2/98) to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-([(2S)-1-(methylsulfonyl)pyrrolidin-2-yl]methoxy)quinazoline (105 mg, 59%).
Reaction SMILES: [NH2:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15]Br.ClCCl>CN(C=O)C>[N+:7]([C:6]1[CH:5]=[N:4][N:3]2[CH2:15][CH2:14][CH2:13][NH:1][C:2]=12)([O-:9])=[O:8]
Reactant: BrCCCBr
Reactant: Nc1n[nH]cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1cnn2c1NCCC2
Temperature: 0 °C
Yield: 87.7 %

Procedure:
A solution of 51.2 g (0.4 moles) 3-amino-4-nitropyrazole in 650 ml dried DMF is slowly added by drops to a suspension of 10 g (0.4 moles) sodium hydride in 200 ml dried DMF. After the reaction is concluded, 121 g (0.6 moles) 1,3-dibromopropane in 250 ml DMF are added. The mixture is then heated for 5 hours accompanied by reflux. After cooling, the preparation is reduced to dryness. When the residue is treated with 300 ml dichloromethane and subsequently cooled to 0° C. the product is precipitated out together with NaBr. The raw product is recrystallized from 1200 ml ethanol. 59 g (38%) ocher-colored crystals with a melting point of 251°-252° C. are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][O:29][C:30]2[C:35]([F:36])=[CH:34][CH:33]=[C:32]([F:37])[C:31]=2[Cl:38])=[CH:22][CH:21]=1)[C:4]([N:6]([CH:16]1[CH2:18][CH2:17]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[Cl:15])=[O:5].[CH:39](=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:39]([NH:1][CH2:2][CH:3]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][O:29][C:30]2[C:35]([F:36])=[CH:34][CH:33]=[C:32]([F:37])[C:31]=2[Cl:38])=[CH:22][CH:21]=1)[C:4]([N:6]([CH:16]1[CH2:17][CH2:18]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[Cl:15])=[O:5])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: NCC(Cc1ccc(CCCOc2c(F)ccc(F)c2Cl)cc1)C(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Reactant: O=Cc1ccccc1
Product: O=C(C(CNCc1ccccc1)Cc1ccc(CCCOc2c(F)ccc(F)c2Cl)cc1)N(Cc1cccc(Cl)c1Cl)C1CC1

Procedure:
Prepared according to the procedure described in Example 17 but using instead 3-amino-2-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]benzyl}-N-cyclopropyl-N-(2,3-dichlorobenzyl)propanamide (Example 15) and benzaldehyde. The title compound was obtained as a colorless oil. MS (ESI+): 670.8.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].CS(O[CH2:13][CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[CH3:15])(=O)=O>CN(C)C=O>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[CH:14]([CH3:15])[CH2:13][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: CC(COS(C)(=O)=O)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Cn1cncn1)c1ccc(Cl)cc1Cl
Reaction time: 6 h
Yield: 58 %

Procedure:
To a stirred mixture of 14 parts of 1H-1,2,4-triazole and 225 parts of N,N-dimethylformamide are added 6.2 parts of a sodium hydride dispersion 78%. When foaming has ceased, there are added 19.5 parts of 2-(2,4-dichlorophenyl)propyl methanesulfonate and stirring is continued for 6 hours at reflux. The reaction mixture is cooled, poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed with water, dried, filtered and evaporated. The residue is crystallized from petroleumether. The product is filtered off and dried, yielding 10.2 parts (58%) of 1-[2-(2,4-dichlorophenyl)propyl]-1H-1,2,4-triazole; mp. 79.5° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:34][C@@H:35]([C@H:46]([OH:55])[C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=1)[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37].[NH:56]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[C@H:57]([C:60](O)=[O:61])[CH2:58][OH:59]>CN(C=O)C>[C:66]([O:65][C:63]([NH:56][C@@H:57]([CH2:60][OH:61])[C:58]([NH:34][C@@H:35]([C@H:46]([OH:55])[C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=1)[C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:37])=[O:59])=[O:64])([CH3:69])([CH3:68])[CH3:67]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: COc1ccc([C@@H](O)[C@H](N)C(=O)OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
Sequentially HATU (645 mg, 1.70 mmol) and DIEA (0.99 mL, 5.7 mmol) were added to a 0° C. solution of (2S,3R)-benzyl 2-amino-3-hydroxy-3-(4-methoxyphenyl)propanoate (HCl salt, 477 mg, 1.41 mmol) and Boc-Ser-OH (290 mg, 1.41 mmol) in DMF (8 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 30 min. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=2:1) twice to afford (2S,3R)-benzyl 2-((S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanamido)-3-hydroxy-3-(4-methoxyphenyl)propanoate (646 mg, 93% yield) as a colorless solid.