Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]=O)[CH:38]=4)[C:33]([CH3:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C([N:54]1[CH2:59][CH2:58][NH:57][CH2:56][C@@H:55]1[CH3:60])(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:57]5[CH2:58][CH2:59][NH:54][C@H:55]([CH3:60])[CH2:56]5)[CH:38]=4)[C:33]([CH3:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:24][CH2:25]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(C=O)c2)c1)C(=O)C1(C(N)=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(CN3CCN[C@H](C)C3)c2)c1)C(=O)C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
A mixture of N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide (55 mg, 0.088 mmol), (S)—N1-Boc-2-methyl-piperazine (17.69 mg, 0.088 mmol), sodium triacetoxyborohydride (37.4 mg, 0.177 mmol) and acetic acid (6.07 μL, 0.106 mmol) in DCM (2 mL) was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were concentrated under vacuum to give the crude residue. It was re-dissolved in 25% TFA in DCM (2 mL) and stirred at room temperature for 2 h. Solvent was evaporated under a stream of nitrogen and then purified with a Gilson HPLC (with 0.1% TFA in the solvents), eluting with 10 to 60% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined, washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(6-methyl-3′-{[(3R)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide as a solid (35 mg, 56.1%). LC-MS m/z 707 (M+H)+, 0.74 min (ret time).
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)=[CH2:9].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:42]1[CH:47]=[CH:46][C:45]([CH:48]([CH3:62])[C:49]([C:55]2[CH:60]=[CH:59][N:58]=[C:57]([CH3:61])[CH:56]=2)([OH:54])[C:50]([F:53])([F:52])[F:51])=[C:44]([Cl:63])[CH:43]=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:63][C:44]1[CH:43]=[C:42](/[CH:9]=[CH:8]/[C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH:47]=[CH:46][C:45]=1[CH:48]([CH3:62])[C:49]([OH:54])([C:55]1[CH:60]=[CH:59][N:58]=[C:57]([CH3:61])[CH:56]=1)[C:50]([F:52])([F:53])[F:51]
Reactant: C=Cc1ccc(C(=O)O)cc1
Reactant: Cc1cc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C(O)(C(C)c2ccc(/C=C/c3ccc(C(=O)O)cc3)cc2Cl)C(F)(F)F)ccn1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Triethyl amine (0.02 ml), 4-vinylbenzoic acid (CAS Reg. No. 1075-49-6, 19 mg), tri-o-tolylphosphine (2 mg) and palladium acetate (1 mg) were added to a solution of 3-(4-bromo-2-chloro-phenyl)-1,1,1-trifluoro-2-(2-methyl-pyridin-4-yl)-butan-2-ol (Example 60 step 1, 41 mg) in DMF (1 ml). The mixture was stirred at 100° C. for 3 h. Water was added and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, 0->100% EtOAc/heptane) to give the title compound (28 mg) as an orange oil. MS (m/e)=476.1 [M+H+].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].O>CN(C=O)C>[CH2:24]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:15][CH2:8][CH2:9][CH3:10]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccc(C=O)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 313.8 %

Procedure:
Potassium carbonate (24.8 g, 180 mmol) was added to a solution of 4-hydroxybenzaldehyde (3.66 g, 30 mmol) in DMF (90 mL) at room temperature. After the mixture was stirred at 60° C. for 1 h, 1-bromooctane (8.7 mL, 36 mmol) was added slowly. The reaction mixture was stirred overnight at 80° C. under N2, cooled to room temperature, and poured over 200 mL of icy water. The mixture was extracted with EtOAc (3×50 mL). The combined organic phase was washed with brine (100 mL), dried over MgSO4, and concentrated in vacuo to give a yellow oil (13.67 g). 1H NMR (400 MHz, CDCl3, δ): 9.88 (s, 1H), 7.84 (d, J=8.7 Hz, 2H), 7.00 (d, J=8.7 Hz, 2H), 4.06 (t, J=6.6 Hz, 2H), 1.83-1.76 (m, 2H), 1.62-1.23 (m, 18H), 0.90 (t, J=8.8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:19]=[C:18]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27]C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[N:17]=[C:16]3[C:12]=1[N:13]=[CH:14][N:15]3C(OC(C)(C)C)=O)[CH2:6][CH2:5]2.Cl.CO.ClCCl>CO.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:19]=[C:18]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]3)[N:17]=[C:16]3[C:12]=1[N:13]=[CH:14][NH:15]3)[CH2:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(N)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc2c(c1)CCN2c1nc(N[C@H]2CC[C@H](N)CC2)nc2[nH]cnc12
Reaction time: 48 h

Procedure:
200 mg of product obtained in stage 4 of example 41 are dissolved in 5 ml of methanol. 5 ml of a 2N solution of hydrochloric acid in methanol are added. Stirring is carried out for 48 hours at ambient temperature, followed by evaporation to dryness. The residue is chromatographed on a silica column, eluting with 85/15/1.5 dichloromethane/methanol/aqueous ammonia. The product obtained is taken up in 10 ml of a 50/50 methanol/dichloromethane mixture, 6 ml of 1M HCl solution in ethyl acetate are added, the mixture is left to crystallize, filtration is carried out, and 87 mg of expected product are thus recovered.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=2)=[CH:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=2)=[CH:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc(-c2cncc(C)c2)cnc1Cl
Reactant: OB(O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2cncc(C)c2)cnc1-c1ccccc1F
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 6-chloro-5′-methyl-3,3′-bipyridine-5-carboxylate (3-2, 4.25 g, 16.16 mmol) in degassed dimethylformamide (81 mL) at 25° C. was added 2-fluorophenylboronic acid (2.94 g, 21.01 mmol), PdCl2dppf (1.18 g, 1.62 mmol) and 4M aqueous cesium carbonate (10.1 mL, 40.4 mmol). The reaction flask was purged with nitrogen, sealed and stirred for 4 hours at 40° C. The crude reaction mixture was partitioned between water and EtOAc, separating layers and washing the organic layer with saturated sodium bicarbonate solution and brine. The solvent was removed by rotary evaporation and the crude product was taken up in DCM (40 mL). Quadrapure TU (6 g) was added and the mixture was stirred overnight at room temperature. Filtration and concentration afforded the title compound (3-3) as a solid. ESI+MS [M+H]+ C19H15FN2O2=323.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([S:15][CH3:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:4]=1[C:17](=[O:30])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([S:15]([CH3:16])=[O:39])[C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:4]=1[C:17](=[O:30])[NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)SC
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)S(C)=O
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To a solution of 1.50 g of methyl 3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-2-(methylthio)propionate in 30 ml of methylene chloride were added 800 mg of mCPBA under cooling with ice, and the mixture was stirred for 30 minutes. The reaction mixture was washed with saturated aqueous solution of sodium bicarbonate and saturated brine in sequence and dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and the residue obtained was purified by means of column chromatography (silica gel, methylene chloride:methanol=100:1 to 50:1) to obtain 1.22 g of methyl 3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-2-(methylsulfinyl)-propionate as colorless crystals. To a solution of 1.02 g of methyl 3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]-carbamoylphenyl]-2-(methylsulfinyl)propionate obtained in 20 ml of methylene chloride were added 550 mg of mCPBA under cooling with ice, and the mixture was stirred for 7 hours at room temperature. The reaction mixture was washed with saturated aqueous solution of sodium bicarbonate and saturated brine in sequence and dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and the crystals obtained were recrystallized from hexane-ethyl acetate to obtain 750 mg of methyl 3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-2-(methylsulfonyl)propionate as colorless crystals. Melting point 144-145° C.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:20]=O)=[N:9]2)=[CH:4][CH:3]=1.[NH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[NH2:23]>CCO>[Br:1][C:2]1[C:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:20]=[N:23][NH:22][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: NNc1ccccn1
Reactant: CC(C)(C)[Si](C)(C)Oc1c(Br)ccc2ccc(C=O)nc12
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1c(Br)ccc2ccc(C=NNc3ccccn3)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.9 %

Procedure:
To the product from Step C (2.95 g, 8.05 mmol) was added EtOH (30 mL, anhydrous). To this solution was added 2-hydrazinylpyridine (0.967 g, 8.86 mmol). The mixture was stirred at ambient temperature for 24 hours. The resulting precipitate was isolated by vacuum filtration and washed with cold EtOH and then dried in vacuo to afford 2.98 g (73%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC1C=CC(S(O[CH:32]2[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:13](=[O:16])[N:14]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCC1(CC)C(=O)NN=C1c1ccc(OC)c(OC)c1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: CCC1(CC)C(=O)N(C2CCNCC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
Prepared analogously as described for the example B1 (Alternative 1) using 5-(3,4-dimethoxyphenyl)-4,4-diethyl-2,4-dihydro-3H-pyrazol-3-one (compound C7) and tert-butyl 4-(Toluene-4-sulfonyloxy)piperidine-1-carboxylate (compound E1) as starting compounds resulting in the title compound. (compound B7)
Reaction SMILES: [OH2:1].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[OH2:13]>ClC1C=CC=CC=1Cl>[CH3:3][C:2]([CH3:7])=[CH:12][C:2]1[CH:7]=[CH:6][C:5]([CH:5]([CH3:6])[C:4]([OH:13])=[O:1])=[CH:4][CH:3]=1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1Cl
Product: CC(C)=Cc1ccc(C(C)C(=O)O)cc1
Temperature: 25 °C

Procedure:
A solution of p-toluenesulphonic acid monohydrate (8.4 g) in o-dichlorobenzene (60 ml) was heated at 110° to 120° and treated dropwise with a previously prepared solution of 2-[4-(1-hydroxy-2-dimethylethyl)phenyl]propionic acid (9 g) in o-dichlorobenzene (40 ml) over a period of 20 minutes at the same temperature. The reaction mixture was rapidly cooled to room temperature, poured into water and extracted several times with ether. The combined ethereal extracts were washed with water and then treated with a 5% solution of NaOH. The separated aqueous phase was acidified with a 10% solution of hydrochloric acid and extracted again with ether and the organic phase was separated.
Reaction SMILES: [C:1]([CH:4]([CH2:9][CH:10]=[C:11]([CH3:26])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:25])[CH2:16][O:17][Si:18]([CH3:24])([CH3:23])[C:19]([CH3:22])([CH3:21])[CH3:20])C(OC)=O)(=[O:3])[CH3:2].[I-].[Na+].O>CN(C)P(=O)(N(C)C)N(C)C>[CH3:26][C:11]([CH2:12][CH2:13][CH:14]=[C:15]([CH3:25])[CH2:16][O:17][Si:18]([CH3:24])([CH3:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:10][CH2:9][CH2:4][C:1](=[O:3])[CH3:2]
Reactant: COC(=O)C(CC=C(C)CCC=C(C)CO[Si](C)(C)C(C)(C)C)C(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CC(=O)CCC=C(C)CCC=C(C)CO[Si](C)(C)C(C)(C)C
Temperature: 150 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a solution of methyl 2-acetyl-10-(dimethyl t-butylsilyl)oxy-5,9-dimethyl-4,8-decadienate (96 mg, 0.25 mmol) in hexamethylphosphoric triamide (0.5 ml) were added sodium iodide (45 mg, 0.30 mmol) and water (0.01 ml), and the mixture was stirred at 150° C. After two hours, the reaction mixture was allowed to cool to room temperature, and water (2 ml) was added thereto. The product was extracted with ether (5 mlx2). The extract was dried over Na2SO4, and concentrated to give a residue, which was then purified with silica gel column chromatography to obtain 6,10-dimethyl-11-(dimethyl t-butylsilyl)oxy-5,9-undecadien-2-one (57 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4](Cl)[N:3]=1.[NH3:18].O>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:18])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: N
Solvent: CC(C)O
Solvent: O
Product: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Reaction time: 8 h

Procedure:
2,6-Dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (36.9 g) was heated with 2M ammonia in isopropanol (250 ml) at 50° C. for 5 hours. After standing at ambient temperature overnight, a further quantity of 2M ammonia in isopropanol (100 ml) was added to break up the resultant cake and the reaction mixture was heated for a further 9 hours until the reaction was complete. To the reaction mixture was added water (70 ml) and the yellow solid filtered off. The solid was washed with isopropyl alcohol:water (5:1 (v/v), 60 ml) and then air-dried under suction to give a first crop. The filtrate was re-filtered after standing overnight to isolate precipitate and both solids were dried in vacuo. The first crop was pure with the second crop material showing a very minor impurity (isolated broad signal 3.5 ppm not seen in first crop) but was otherwise identical. Solid first crop (28.4 g), solid second crop (3.42 g).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20]2[S:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:14][CH2:13]1.[CH3:29]N(C)C=O.[H-].[Na+].IC>O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][N:19]([CH3:29])[C:20]2[S:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:14][CH2:13]1
Reactant: c1ccc2c(c1)OCC(CN1CCC(CNc3nc4ccccc4s3)CC1)O2
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CN(CC1CCN(CC2COc3ccccc3O2)CC1)c1nc2ccccc2s1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 11.85 parts of N-[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinylmethyl]-2-benzothiazolamine in 72 parts of N,N-dimethylformamide were added portionwise 1.5 parts of a sodium hydride dispersion 50%. Upon completion, stirring was continued for 30 minutes. A solution of 4.6 parts of iodomethane in 18 parts of N,N-dimethylformamide was added dropwise. The whole was stirred overnight at room temperature. The reaction mixture was poured into water and the product was extracted twice with 4-methyl-2-pentanone. The combined organic layers were dried, filtered and evaporated. The residue was separated by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The first fraction was collected and the eluent was evaporated. The residue was crystallized from a mixture of acetonitrile and 1,1'-oxybisethane, yielding 1 part of N-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]-N-methyl-2-benzothiazolamine; mp. 125.4° C. (compound 62).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH3:11])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20].O>O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:20])[O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])[N:7]([CH3:11])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cn1nc(C(C)(C)C)cc1N
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a solution of 3-tert-butyl-1-methyl-1H-pyrazole-5-amine (500 g, 3.26 mmol) and pyridine (0.310 ml, 3.92 mmol) in tetrahydrofuran (11 ml) was added 2,2,2-trichloroethyl chloroformate (0.542 ml, 3.92 mmol) with ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 925 mg (86.5%) of the desired product as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:19][CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:17]=1[Br:18])[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:35]([NH2:38])[C:36]#[CH:37]>ClCCl.C(OCC)(=O)C.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:19][CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:17]=1[Br:18])[C:12]([NH:38][CH2:35][C:36]#[CH:37])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCOc1cc(C(=O)O)cc(OCc2ccccc2)c1Br
Reactant: C#CCN
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C#CCNC(=O)c1cc(OCOCC[Si](C)(C)C)c(Br)c(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a mixture of 3-(benzyloxy)-4-bromo-5-((2-(trimethylsilyl)ethoxy)methoxy)benzoic acid (6.142 g, 13.55 mmol) and Mukaiyama reagent (2-chloro-1-methylpyridinium iodide, 5.19 g, 20.3 mmol) in dichloromethane (135 mL) was added triethylamine (7.55 mL, 54.2 mmol). The solution was stirred for 10 minutes after which time propargylamine (1.74 mL, 27.1 mmol) was added. The solution was stirred overnight. The solution was diluted with 1:1 ethyl acetate/diethyl ether and washed with water, brine, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography (40 g silica gel, gradient of ethyl acetate in dichloromethane) providing 3-(benzyloxy)-4-bromo-N-(prop-2-ynyl)-5-((2-(trimethylsilyl)ethoxy)-methoxy)-benzamide as an orange oil (6.49 g). MS (M+1)=492.2. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.28-7.55 (m, 5H) 7.13 (dd, J=11.37, 1.77 Hz, 2H) 6.23 (br. s., 1H) 5.34 (s, 2H) 5.20 (s, 2H) 4.22 (dd, J=5.05, 2.53 Hz, 2H) 3.81 (dd, J=9.09, 7.58 Hz, 2H) 2.28 (t, J=2.78 Hz, 1H) 0.91-1.00 (m, 2H) −0.03-0.03 (m, 9H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:11]([CH2:49][CH:50]([CH3:52])[CH3:51])[C:12]([C:14]1[CH:48]=[CH:47][C:17]2[N:18]([CH2:34][CH2:35][CH2:36][N:37]([CH3:46])[CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)[C:19]([NH:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)=[N:20][C:16]=2[CH:15]=1)=O)[CH:8]([CH3:10])[CH3:9].C(OCC)(=O)C>O1CCCC1>[CH2:7]([N:11]([CH2:12][C:14]1[CH:48]=[CH:47][C:17]2[N:18]([CH2:34][CH2:35][CH2:36][N:37]([CH3:46])[CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)[C:19]([NH:21][C:22]3[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=3)=[N:20][C:16]=2[CH:15]=1)[CH2:49][CH:50]([CH3:51])[CH3:52])[CH:8]([CH3:10])[CH3:9]
Reactant: COc1cc(Nc2nc3cc(C(=O)N(CC(C)C)CC(C)C)ccc3n2CCCN(C)CCc2ccccn2)cc(OC)c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3cc(CN(CC(C)C)CC(C)C)ccc3n2CCCN(C)CCc2ccccn2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A molar solution of lithium aluminium hydride in tetrahydrofuran (0.83 ml, 5 eq) is added dropwise to a solution of N,N-diisobutyl-1-{3-[methyl(2-pyridin-2-ylethyl) amino]propyl}-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide (105 mg, 1 eq. prepared according to Example A1) cooled down to 0° C., in tetrahydrofuran (3 ml). After stirring for 15 minutes at 0° C., the mixture is heated at 60° C. for 3 hours then cooled down to 0° C. and hydrolysed. After adding ethyl acetate, decanting and extraction, the combined organic phases are washed with salt water, followed by drying over sodium sulphate and concentrating under reduced pressure. Purification by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 9:1) produces the expected compound in the form of a foam (63 mg, 62% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:18]=1)=[CH2:16])[C:10]([O:12]CC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>C(COC)OC.O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:18]=1)=[CH2:16])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C(c1cccc(OC2CCCCO2)c1)C(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: C=C(c1cccc(OC2CCCCO2)c1)C(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A solution of ethyl 2-(tert-butoxycarbonylamino)-3-(3'-tetrahydropyranyloxyphenyl)-3-butenoate (0.40 g) in dimethoxyethane (10 ml) and water (2 ml) is treated with solid lithium hydroxide monohydrate (0.02 g). After stirring for 2 hours at room temperature, the mixture is diluted with water and acidified with 0.1 N hydrochloric acid to ca pH 4. Extraction with ether gives essentially pure racemic 2-(tert-butoxycarbonylamino)-3-(3'-tetrahydropyranyloxyphenyl)-3-butenoic acid (0.25 g): colorless solid.