Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.CO.[BH4-].[Na+]>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:15]1
Reactant: CCOC(=O)N1CCC(=Nc2c(Cl)cccc2Cl)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Product: CCOC(=O)N1CCC(Nc2c(Cl)cccc2Cl)CC1
Reaction time: 1 h

Procedure:
To a stirred and refluxing mixture of 250 parts of ethyl 4-[(2,6-dichlorophenyl)imino]-1-piperidinecarboxylate in 160 parts of methanol and 160 parts of 2-propanol are added portionwise 30 parts of sodium borohydride. Upon completion, stirring at reflux temperature is continued for one hour. The warm reaction mixture is poured onto water and the product is extracted with methylbenzene. The extract is dried and evaporated. The residue is crystallized from a mixture of 160 parts of 2,2'-oxybispropane and 160 parts of petroleumether, yielding 96 parts of ethyl 4-[(2,6-dichlorophenyl)amino]-1-piperidinecarboxylate; mp. 107.2°-116.6° C.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=[O:14].[CH3:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([OH:35])[CH2:28][N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:21][C:19]=2[N:20]=1>CC(O)=O>[OH:35][C@@H:27]([CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:18]2[S:17][C:16]([CH3:15])=[N:20][C:19]=2[CH:21]=1)[CH2:28][N:29]1[CH2:30][CH2:31][N:32]([CH2:1][CH:2]2[CH2:6][C:5](=[O:7])[N:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:3]2=[O:14])[CH2:33][CH2:34]1
Reactant: Cc1nc2cc(OCC(O)CN3CCNCC3)ccc2s1
Reactant: C=C1CC(=O)N(c2ccccc2)C1=O
Solvent: CC(=O)O
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CC4CC(=O)N(c5ccccc5)C4=O)CC3)ccc2s1

Procedure:
A solution of 3-methylene-1-phenylazolidine-2,5-dione (250 mg, 1.33 mmol) and 1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol (415 mg, 1.35 mmol) in AcOH (10 mL, glacial) was stirred 14 hours at 50° C. Concentrated in the Savant™ and residue taken up in EtOAc and washed with NaHCO3 (sat. aq. soln.), H2O and brine, dried over MgSO4, filtered and concentrated. Purification via flash column chromatography (gradient 5 to 10% MeOH/EtOAc) afforded 3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)-1-phenylazolidine-2,5-dione.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:14]=2)[C:11](=[O:25])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:26])[N:4]=1.Cl[C:28]1[C:29]2[CH:36]=[CH:35][NH:34][C:30]=2[N:31]=[CH:32][N:33]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:31]1[C:30]2[NH:34][CH:35]=[CH:36][C:29]=2[C:28]([NH:1][CH2:2][C:3]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([F:22])([F:23])[F:24])[CH:14]=3)[C:11](=[O:25])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[F:26])[N:4]=2)=[N:33][CH:32]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: NCc1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c2c(F)cccc2nc(CNc2ncnc3[nH]ccc23)n1-c1cccc(OCC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 36 h
Yield: 20.6 %

Procedure:
Under nitrogen, to 2-(aminomethyl)-5-fluoro-3-(3-(2,2,2-trifluoroethoxy)phenyl)quinazolin-4(3H)-one (73 mg, 0.20 mmol, 1.0 equiv) in t-BuOH (0.2 mL) at 23° C. was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (34 mg, 0.22 mmol, 1.1 equiv) and diisopropylethylamine (70 μL, 0.40 mmol, 2.0 equiv). After stirring for 36 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 20 mg of the title compound (21% yield).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:13])[CH:9]=[C:10]([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH3:12][C:10]1([CH3:11])[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[NH:7][C:8](=[O:13])[CH2:9]1
Reactant: CC(C)=CC(=O)Nc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CC(=O)Nc2ccccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To 3-methyl-but-2-enoic acid phenylamide (7.6 g, 43 mmol) in DCM (100 mL) was added AlCl3 (8.7 g, 65.2 mmol) and the mixture was stirred at 50° C. for 2 hrs. After cooling to rt, the mixture was treated with 1N HCl (50 mL) and extracted with DCM (30 mL×2). This solution was then washed with brine (50 mL×2) and dried over MgSO4. The filtrate was evaporated to afford 4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one as a brown solid in quantitative yield (7.6 g). MS: 176.0 (M+H)+; tR=1.91 min (method 1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:36])[CH2:33][C:34]#[N:35])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12.N1[CH2:42][CH2:41][CH2:40][CH2:39]C1.C1(C=O)CC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32]([C:33](=[CH:39][CH:40]4[CH2:42][CH2:41]4)[C:34]#[N:35])=[O:36])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12
Reactant: C1CCNCC1
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4c(F)cccc4F)cc3)c3c(N)ncnc32)C1
Agent: O=CC1CC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4c(F)cccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 21.4 %

Procedure:
Into a 10 mL sealed tube, was placed a solution of 3-[(3R)-3-[4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (150 mg, 0.31 mmol, 1.00 equiv) in methanol (5 mL), piperidine (78 mg, 0.92 mmol, 3.0 equiv), and cyclopropanecarbaldehyde (64 mg, 0.91 mmol, 3.0 equiv). The resulting solution was stirred for 12 h at 25° C. and then concentrated under vacuum. The residue was diluted with 10 mL of dichloromethane, and the solution was washed with saturated aqueous ammonium chloride, water and brine. The organics were dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (20/1) to give 36 mg (21%) of 2-[[(3R)-3-[4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]carbonyl]-3-cyclopropylprop-2-enenitrile as a white solid.
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][C:16](SC)=[NH:17])[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[N:20]#[C:21][NH2:22]>CO>[C:21]([N:22]=[C:16]([NH2:17])[CH2:15][C:12]1[CH:13]=[CH:14][C:7]2[S:6][C:5]3[N:4]=[CH:3][CH:2]=[N:1][C:10]=3[NH:9][C:8]=2[CH:11]=1)#[N:20]
Reactant: N#CN
Reactant: CSC(=N)Cc1ccc2c(c1)Nc1nccnc1S2
Solvent: CO
Product: N#CN=C(N)Cc1ccc2c(c1)Nc1nccnc1S2
Yield: 73.5 %

Procedure:
To 15 ml of a solution of 410 mg of methyl (10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetothioimidate in methanol was added 250 mg of cyanamide and the resulting mixture was heated to 60° C. or below for 1 hour. Then the reaction mixture was brought back to room temperature and the solvent was distilled off under reduced pressure to reduce its amount. The crystals thus precipitated were taken up by filtration and washed successively with methanol and ethyl acetate. Thus, 295 mg of the title compound was obtained as yellow crystals.
Reaction SMILES: [S:1]([O-])(O)=O.[Na+].[CH2:6]([S:11]([C:14]1[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:7]([CH3:10])([CH3:9])[CH3:8]>CN1CCCC1=O>[CH2:6]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([SH:1])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: O=S([O-])O
Reactant: CC(C)(C)CS(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)CS(=O)(=O)c1ccc(S)cc1
Temperature: 100 °C
Yield: 96 %

Procedure:
14.4 g (0.194 mol) of sodium hydrogen sulphite (NaSH·H2O) in 120 ml of N-methylpyrrolidone are introduced and the water is removed at 160° C. with nitrogen. The mixture is cooled to 100° C., 20 g (0.081 mol) of 4-(neopentylsul-phonyl)-chlorobenzene are added, and the mixture is further reacted at 125° C. for 5 hours and the solvent is distilled off under reduced pressure. The residue is dissolved in 150 ml of water and acidified at 10°-20° C. with half-concentrated hydrochloric acid. The mixture is extracted with 100 ml of methylene chloride, the organic phase is washed neutral with water, dried with magnesium sulphate, concentrated and, after addition of 50 ml of toluene, distilled at 0.1 mbar up to an inside temperature of 130° C. to give 19 g of 4-(neopentylsulphonyl)-thiophenol of boiling point: 130° C./0.1 mbar; purity by gas chromatography: 98.6%=95% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][N:8]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:48](OC(=O)C)(=[O:50])[CH3:49]>CN(C=O)C>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH:30][C:48](=[O:50])[CH3:49])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:37][CH:36]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(N)nc3)n2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(NC(C)=O)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
A solution of N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-yl)pyridine-2,5-diamine (0.0551 g, 0.097 mmol) and pyridine (0.05 mL, 0.618 mmol) in DMF (2 mL) was treated dropwise with acetic anhydride (Aldrich) (10.0 μl, 0.107 mmol) at 0° C. The orange solution was stirred at rt overnight. The mixture was concentrated in vacuo to reduce the solvent volume to about 1 mL. Water (2 mL) and brine (20 mL) were added and the aqueous phase was extracted with 25% iPrOH in CHCl3+1% NH4OH (2×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give N-(5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-ylamino)pyridin-2-yl)acetamide (0.060 g, 100% yield) as a yellow powder. 1H NMR (300 MHz, CDCl3) δ 11.88 (s, 1H); 8.75 (d, J=2.19 Hz, 1H); 8.47 (s, 1H); 8.24 (d, J=2.34 Hz, 1H); 8.06-8.16 (m, 1H); 7.86-7.95 (m, 1H); 7.83 (br. s., 1H); 7.19 (t, J=8.48 Hz, 4H); 6.87 (d, J=6.58 Hz, 4H); 4.84 (d, J=10.96 Hz, 4H); 3.80 (d, J=4.09 Hz, 6H); 2.59 (s, 3H); 2.20 (s, 3H). m/z (ESI, +ve ion) 611.2 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12](=[O:31])[NH:13][C:14]([CH3:30])([CH3:29])[CH2:15][N:16]([C:25](=[O:28])[CH2:26]Br)[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[CH3:24])([CH3:10])([CH3:9])[CH3:8].[Cl-].[NH4+]>O1CCCC1.O>[C:7]([O:11][C:12]([N:13]1[CH2:26][C:25](=[O:28])[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[CH3:24])[CH2:15][C:14]1([CH3:30])[CH3:29])=[O:31])([CH3:10])([CH3:9])[CH3:8]
Reactant: Cc1c(F)cccc1N(CC(C)(C)NC(=O)OC(C)(C)C)C(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(F)cccc1N1CC(C)(C)N(C(=O)OC(C)(C)C)CC1=O
Reaction time: 0.17 h
Yield: 47.1 %

Procedure:
A solution of 1.7 g of potassium t-butoxide (15.1 mmol) in tetrahydrofuran (100 ml) was added to a solution of 4.2 g of {2-[(2-bromoacetyl)-(3-fluoro-2-methylphenyl)amino]-1,1-dimethylethyl}carbamic acid t-butyl ester obtained in Example (67b) (10.1 mmol) in tetrahydrofuran (100 ml) under a nitrogen atmosphere and under cooling in a dry ice-acetone bath over 30 minutes, and the mixture was stirred at the same temperature for 10 minutes. A saturated ammonium chloride aqueous solution was added to the reaction mixture. The mixture was returned to room temperature and diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/ethyl acetate=5/1) to obtain 1.6 g of the title compound (yield: 47%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[C:24]([F:25])=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16](Cl)[N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[C:24]([F:25])=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(F)c(N[C@@H]2CCN(Cc3ccccc3)C2)nc1Cl
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)c(F)c1
Reaction time: 1 h
Yield: 66.5 %

Procedure:
To a solution of ethyl 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-chloro-5-fluoronicotinate (500 mg) in ethanol (20 mL) were added ammonium formate (584 mg) and 10% Pd/C (300 mg) at 25° C. and the mixture was heated to reflux with stirring for 1 hour. After cooling, the catalyst in the reaction mixture was removed by filtration. The filtrate was evaporated in vacuo. To the residue were added CH2Cl2 (30 ml), ethanol (7 mL), and benzaldehyde (140 mg) at 25° C. After stirring for 5 minutes, sodium triacetoxyborohydride (280 mg) was added to the mixture. The reaction mixture was stirred at 25° C. for 3 hours, and then poured into a mixture of CH2Cl2 and aqueous NaHCO3. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (11 g) using a mixed solvent of dichloromethane and MeOH (100:1 to 40:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. Title compound (302 mg, 66%) was obtained as colorless syrup.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@H:22]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][C@H:20]([C:32]([OH:34])=O)[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:35]([NH:42][CH2:43][CH:44]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:45]([CH3:47])[CH3:46])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(C(C)C)C(C)C)C.CCCP(=O)=O>CC(N(C)C)=O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@H:22]([NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:21][C@H:20]([C:32](=[O:34])[N:42]([CH2:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH2:43][CH:44]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[CH:45]([CH3:47])[CH3:46])[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Reactant: CC(C)C(CNCc1ccccc1)c1ccccc1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)C(CN(Cc1ccccc1)C(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a stirred, ice-cooled mixture of (3S*,5R*)-5-tert-butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (466.5 mg, 1 mmol), benzyl-(3-methyl-2-phenyl-butyl)-amine (279 mg, 1.1 mmol) and N-ethyldiisopropylamine (1.37 mL, 8 mmol) in dimethylacetamide (6 mL), propylphosphonic anhydride solution (˜50% in DMF, 0.95 mL, ˜1.5 mmol) is added. The reaction mixture is stirred for 7 h at RT and evaporated in vacuo. The residue is dissolved in ethyl acetate and washed twice with an aqueous 10% K2CO3 solution. The organic layer is dried (Na2SO4) and evaporated in vacuo and the residue is purified by flash chromatography (hexane/ethyl acetate). The combined pure fractions are evaporated to afford the title compound as a white amorphous solid. MS: 702.3 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, then 100% CH3CN+0.1% TFA for 2 min, flow 1.5 ml/min): 8.87 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](O)=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.CO>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([CH2:12][OH:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1

Procedure:
To a solution of N-t-butoxycarbonyl isonipecotic acid (15.0 g, 65.4 mmol) from example 3 step A, in anhydrous THF (50 ml), was added borane (65.4 ml of a 1M solution in THF, 65.4 mmol) at room temperature. After 72 hours methanol (50 ml) was added and the solvent evaporated in vacuo. The residue was dissolved in methanol (100 ml) and the solvent evaporated in vacuo. The eesidue was partitioned between EtOAc and NaHCO3, the organic layer separated and washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by chromatography (Silica gel, eluting with 50% EtOAc in hexanes ) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[N:33](S(C2C=CC(C)=CC=2)(=O)=O)[C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:17]2[CH:16]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[NH:33][C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH:24][CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[C:17]2[CH:16]=1
Reactant: COc1cc2c(-c3cc4c(CNCCc5ccccc5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(CNCCc5ccccc5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 32.1 %

Procedure:
[2-(5,6-Dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo-[2,3-b]pyrid-4-ylmethyl]phenylethylamine is prepared as described in Example 179a starting with 0.16 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]phenylethylamine instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 1.2 cm3 of 5N potassium hydroxide. 0.038 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]-phenylethylamine is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH2:3][OH:4].[H-].[Na+].[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:4][CH2:3][C:2]([CH3:5])=[CH2:1])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=C(C)CO
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)COCc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
A solution of 2-methyl-2-propen-1-ol (120) (1.17 mL, 13.9 mmol) in anhydrous DMF (5 mL, then 2×1 mL to rinse) was added to a suspension of 60% NaH (674 mg, 16.9 mmol) in anhydrous DMF (5 mL) under N2 at 0° C. and the mixture was stirred at 0° C. for 30 min. A solution of 4-(benzyloxy)benzyl chloride (3.87 g, 16.6 mmol) in anhydrous DMF (6 mL, then 2×2 mL to rinse) was added and the mixture was stirred at room temperature for 16 h. The resulting mixture was added to ice/aqueous NaHCO3 (100 mL) and extracted with EtOAc (4×100 mL). The extracts were washed with water (100 mL), the EtOAc was removed, and the residual oil was chromatographed on silica gel. Elution with petroleum ether firstly gave foreruns, then further elution with 0-25% CH2Cl2/petroleum ether gave 1-(benzyloxy)-4-{[(2-methyl-2-propenyl)oxy]methyl}benzene (122) (reported by Wennerberg et al., 1999 via alkylation of 4-(benzyloxy)benzyl alcohol) (3.48 g, 93%) as an oil that was used directly in the next step; 1H NMR (CDCl3) δ 7.45-7.28 (m, 5H), 7.27 (dt, J=8.5, 2.4 Hz, 2H), 6.95 (dt, J=8.7, 2.4 Hz, 2H), 5.07 (s, 2H), 4.99 (m, 1H), 4.91 (m, 1H), 4.42 (s, 2H), 3.91 (s, 2H), 1.76 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](=[O:31])([O:19][C:20]1[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[C:28]([F:29])[C:23]=2[O:22][N:21]=1)[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].CN(C)[CH:34]=[O:35]>C1COCC1>[C:13](=[O:31])([O:19][C:20]1[C:24]2[CH:25]=[C:26]([CH:34]=[O:35])[C:27]([F:30])=[C:28]([F:29])[C:23]=2[O:22][N:21]=1)[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)Oc1noc2c(F)c(F)ccc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)Oc1noc2c(F)c(F)c(C=O)cc12
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To a solution of diisopropylamine (3.2 g, 32.4 mmol) in THF (20 mL) was added n-butyl lithium (20.2 mL, 1.6N), dropwise at −10° C. and the solution stirred for 30 min. The reaction mixture was cooled to −78° C. and into this was added, tert-butyl 6,7-difluoro-1,2-benzisoxazol-3-yl carbonate (Intermediate 530, 4.0 g, 14.7 mmol) in THF (20 mL). It was stirred at −78° C. for 2 h and then treated with dimethylformamide (3.2 g, 44.2 mmol) and continued the stirring at −78° C. for 1 hour. The reaction was quenched by the addition of saturated solution of ammonium chloride and then extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water followed by brine and then dried over anhydrous sodium sulfate. The solution was filtered and the filtrate evaporated under vacuum, and the residue was purified over silica gel column using a gradient of ethyl acetate in pet. ether to give product as a yellow solid Yield: 3.0 g (68%).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][NH2:20]>C1COCC1>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:20][CH3:19])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(CBr)cc1
Reaction time: 0.5 h
Yield: 71 %

Procedure:
Mix 4-(bromomethyl)benzenesulfonyl chloride (2.7 g, 10 mmol), anhydrous potassium carbonate (1.4 g, 10 mmol) and anhydrous THF (60 mL) under nitrogen. Cool the mixture in an ice bath, add dropwise a 2M solution of methylamine in THF, and stir at this temperature for 30 min. Remove the ice bath and stir at ambient temperature for 16 h. Dilute with EtOAc then wash with 1N aqueous HCl. Separate the organic layer, dry over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 4:1, 7:3 and 13:7) to obtain the title compound (1.5 g, 71%). MS (ES+) m/z: 266 (M+H)+.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[CH3:1][NH:2][C:3](=[O:4])[O:18][CH:15]1[CH2:16][CH2:17][N:12]([CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:13][CH2:14]1
Reactant: CN=C=O
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: ClC(Cl)Cl
Product: CNC(=O)OC1CCN(Cc2ccccc2)CC1

Procedure:
Methyl isocyanate (8.94 g, 157 mmol) was added to a solution of 1-benzyl-4-piperidinol (10 g, 52.3 mmol) in chloroform (80 ml), and the reaction stirred under reflux for 16 hours. The cooled mixture was concentrated under reduced pressure, the residual solid was triturated from 40–60 petroleum ether, and the product filtered and dried to afford the title compound as a white solid, 1 g. m.p.—106–108° C.