Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:8]([O:9][CH2:10][CH:11]2[CH2:14][CH2:13][CH2:12]2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:15]([O-])=O)[CH:3]=1.[NH4+].[Cl-].[CH:20]([O-])([O-])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.[Zn].C(OCC)(=O)C.CO>[Br:1][C:2]1[C:8]([O:9][CH2:10][CH:11]2[CH2:14][CH2:13][CH2:12]2)=[CH:7][C:5]2[NH:6][CH:20]=[N:15][C:4]=2[CH:3]=1
Reactant: Nc1cc(OCC2CCC2)c(Br)cc1[N+](=O)[O-]
Reactant: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1cc2nc[nH]c2cc1OCC1CCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 49.2 %

Procedure:
To a suspension of 4-bromo-5-(cyclobutylmethoxy)-2-nitroaniline (0.4967 g, 1.649 mmol) in 1:1 ethyl acetate/methanol (17.2 mL) was added saturated NH4Cl solution (1.9 mL). The mixture was cooled to 0° C. in ice bath, and then zinc powder (0.9 g, 10 mmol) was added in two portions over 2 minutes. The reaction mixture was stirred for 5 min, the ice bath was removed, and the flask was allowed to warm to room temperature. The suspension was then stirred for 1 h at 55° C. The reaction mixture was diluted with CH2Cl2, filtered through a Celite plug, and the filter cake was washed with CH2Cl2. The resulting filtrate was washed with saturated solution of NaHCO3. The aqueous layer was then extracted with CH2Cl2 (50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford the crude intermediate as a dark purple oil. To a solution of the crude intermediate in THF (20 mL) was added ethyl orthoformate (0.88 mL, 5.3 mmol) and p-toluenesulfonic acid monohydrate (54.5 mg, 0.286 mmol). The mixture was heated for 1 h at 55° C. The reaction mixture was concentrated, and the resulting residue was diluted with EtOAc (25 ml). This solution was washed with saturated solution of NaHCO3 (25 mL), and the aqueous layer was subsequently extracted with EtOAc (2×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. Recrystallization from 9:1 CH2Cl2/MeOH and hexanes afforded the title compound as a yellow solid (0.2280 g) after collection via filtration. The remaining filtrate was concentrated and suspended in MeOH and 1 M solution of HCl (aq) (60 mL). The aqueous solution was extracted with Et2O (3×30 mL). The aqueous layer was then adjusted to pH 9 using solid K2CO3. The aqueous layer was extracted with CH2Cl2 (3×40 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford a second portion of the title compound as a yellow-brown solid (0.1275 g, 77% overall). 1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 7.78 (s, 1H), 7.19 (s, 1H), 4.01 (d, J=6.0 Hz, 2H), 2.91-2.76 (m, 1H), 2.23-2.11 (m, 2H), 2.10-1.93 (m, 4H). LCMS calculated for C12H14BrN2O (M+H)+: m/z=281.0, 283.0. found: 281.0, 283.0.
Reaction SMILES: [OH-].[Na+].Cl.[C:4](=[NH:9])(OCC)[CH3:5].[NH:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[NH2:11]>C(O)C>[C:4]([NH:11][NH:10][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[NH:9])[CH3:5]
Reactant: CCOC(C)=N
Reactant: CC(C)(C)OC(=O)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=N)NNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium hydroxide (16.0 g, 400 mmol) was dissolved in absolute ethanol (1000 mL) at 60° C. The solution was cooled to 0° C., and treated portion-wise with ethyl ethanimidoate hydrochloride (50 g, 400 mmol); after 10 minutes, tert-butyl hydrazinecarboxylate (52.9 g, 400 mmol) was added in a single portion. The reaction was warmed to 70° C. and was stirred at 70° C. for 2.5 hours. The mixture was then cooled to 20° C. and filtered. The filtrate was concentrated in vacuo and treated with tert-butyl methyl ether (500 mL) and ethanol (20 mL). After seeding, the mixture was allowed to stir for 18 hours, after which time the precipitated solid was collected via filtration and washed with ice-cold tert-butyl methyl ether (500 mL). The solid was dissolved in 2-methyltetrahydrofuran:methanol (9:1 mixture, 300 mL), and the solution was concentrated to dryness. The residue was washed with diethyl ether (3×200 mL) and dried, affording the product as a very pale yellow solid. Yield; 50.2 g, 290 mmol, 72%. LCMS m/z 174.3 (M+1). 1H NMR (500 MHz, CD3OD) δ 1.47 (s, 9H), 1.88 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][OH:9].C(=O)(O)[O-].[Na+].Cl[C:16]([O:18][CH3:19])=[O:17]>C(Cl)Cl>[OH:9][N:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[C:16](=[O:17])[O:18][CH3:19]
Reactant: COC(=O)Cl
Reactant: Cc1ccccc1NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N(O)c1ccccc1C

Procedure:
To a 250 ml 3-neck RBF, stirring under nitrogen atmosphere, was charged 16.1 g (1.0 eq., 0.13 moles) N-2-methylphenylhydroxyamine in 40 ml methylene chloride and 16.8 g (1.5 eq., 0.20 moles) sodium bicarbonate neat. With a pipet added 13.1 g (1.05 eq, 0.37 moles) methyl chloroformate neat to the mixture at -5° C. to +5° C. The reaction mixture was stirred at 0° C. for 30 min. following the addition and the reaction was monitored by GC.
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:6][C:5]1=O)(=O)[CH3:2].N1CCCC1.C(=O)(O)O.[NH2:28][C:29]([NH2:31])=[NH:30]>C(Cl)(Cl)Cl.O1CCOCC1>[NH2:31][C:29]1[N:30]=[C:1]([CH3:2])[C:4]2[C:9](=[O:10])[CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH2:6][C:5]=2[N:28]=1
Reactant: CC(=O)C1C(=O)CC(c2ccc(F)cc2)CC1=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: C1CCNC1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1)C2
Temperature: 25 °C

Procedure:
To a stirred solution of 2-acetyl-5-(4-fluoro-phenyl)-cyclohexane-1,3-dione (200 mg, 0.80 mmol) from stage 1, in chloroform was added pyrrolidine (68 mg, 0.96 mmol). The reaction mixture was stirred at ambient temperature and monitored by TLC until complete disappearance of 2-acetyl-5-(4-fluoro-phenyl)cyclohexane-1,3-dione. The reaction mixture was washed with water (10 ml) and the solvent was removed under reduced pressure to give a solid m=229 mg, mass spectrum (ES-MS (+ve)) 302 [MH]+, Retention time 1.44 min, 100% UV. To a stirred solution of this solid (229 mg, 0.76 mmol) in dioxane (2.5 ml) was added guanidine carbonate (504 mg, 2.8 mmol) and the mixture heated at 100° C. and stirred for 16 h. 1,4-Dioxane was removed by evaporation under reduced pressure, water (5 ml) was added and the resulting precipitate was filtered, washed with water and heptane and air dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([C:28]3[CH:29]=[C:30]([N:34]4[CH2:39][CH2:38][CH:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:36][CH2:35]4)[CH:31]=[N:32][CH:33]=3)=[CH:16][N:17](S(C3C=CC(C)=CC=3)(=O)=O)[C:12]2=[CH:11][CH:10]=1.[OH-].[Na+]>C1COCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([C:28]3[CH:29]=[C:30]([N:34]4[CH2:39][CH2:38][CH:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])[CH2:36][CH2:35]4)[CH:31]=[N:32][CH:33]=3)=[CH:16][NH:17][C:12]2=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(N4CCC(NC(=O)OC(C)(C)C)CC4)c3)c3nc(-c4c(F)cccc4F)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3c[nH]c4ccc(-c5c(F)cccc5F)nc34)c2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
A solution of tert-butyl 1-(5-(5-(2,6-difluorophenyl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (79 mg, 0.120 mmol, 88% pure) in THF (2 mL) was treated with NaOH 5M (0.048 mL, 0.239 mmol). The reaction mixture was heated to reflux (bath temperature 80° C.). After 1 h, NaOH 5M (0.45 mL, 0.96 mmol, 8.0 equiv) was further added. After 23 h, the solution was cooled to 23° C., concentrated in vacuo and purified by silica gel chromatography (eluent: 1-7% MeOH/DCM), affording tert-butyl 1-(5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (31 mg, 51%). MS (ESI, pos. ion) m/z: 506.2 (M+1). A solution of tert-butyl 1-(5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (31 mg, 0.061 mmol) in MeOH (0.5 mL) was treated with HCl, 5-6n in IPA (0.123 mL, 0.613 mmol). The reaction was heated to 50° C. under N2. After 2 h, the reaction was cooled to 23° C. and the product (as HCl salt) was free-based using a Silicycle Si-propylsulfonic acid ion exchange column (catalog # R51230B). The compound was slurried in MeOH/DCM and added to a pad of the resin (wetted and flushed with 10 mL MeOH). It was flushed with MeOH (50 mL), and then the product was “released” using 2.0 M NH3 in MeOH solution (50 ml). The final filtrate was concentrated, affording 1-(5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-amine MS (ESI, pos. ion) m/z: 406.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][O:24][CH2:25][C:26]([NH2:28])=[O:27].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].C>C1(C)C=CC=CC=1.CC1C=CC(C)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][O:24][CH2:25][C:26]([NH2:28])=[O:27])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: NC(=O)COCCCl
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: C
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: Cc1ccc(C)cc1
Product: NC(=O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1

Procedure:
15 g (0.0523 mole) of dextrorotatory (+)-1-[(4-chlorophenyl)phenylmethyl]piperazine (prepared in Example 4.2), 8.3 g (0.0601 mole) of 2-(2-chloroethoxy)acetamide, 12.8 g (0.1203 mole) of sodium carbonate and 0.5 g (0.0030 mole) of potassium iodide are added to a mixture of 100 ml of p-xylene and 150 ml of toluene. The mixture is heated at reflux temperature for 17 hours. A small amount of Norit is added and the mixture is filtered while hot through Dicalite. The residue on the filter is washed with a small amount of toluene and the filtrate and washing solution are combined. The solvents are evaporated and the residue is taken up in 100 ml of toluene. The organic phase is washed successively with 100 ml of water and twice with 100 ml of a saturated aqueous solution of sodium chloride. The organic phase is separated off and the solvent evaporated. At this point, the crude residue obtained could be purified in a manner similar to that described at point 9 above, in order to obtain dextrorotatory (+)-2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetamide in the form of the free base. However, if desired, the crude residue may also be converted to the corresponding dihydrochloride in the following manner: the crude residue obtained is taken up in 100 ml of acetone, cooled in an ice bath and 15 ml of concentrated hydrochloric acid are added dropwise thereto. A further 200 ml of acetone are added and the mixture is cooled and stirred on an ice bath for 1 hour. The precipitate is filtered off and dried under vacuum at 50° C. 19 g of the levorotatory dihydrochloride of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetamide are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:10])=[CH:4][C:3]=1Br.[CH3:17][C:18]1([CH3:27])[CH2:23][CH2:22][C:21](B(O)O)=[CH:20][CH2:19]1>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>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:10])=[CH:4][C:3]=1[C:21]1[CH2:22][CH2:23][C:18]([CH3:27])([CH3:17])[CH2:19][CH:20]=1
Reactant: Nc1ccc(CC(=O)NCCCO)cc1Br
Reactant: CC1(C)CC=C(B(O)O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC1(C)CC=C(c2cc(CC(=O)NCCCO)ccc2N)CC1

Procedure:
The title compound was prepared from 2-(4-amino-3-bromo-phenyl)-N-(3-hydroxy-propyl)-acetamide (as prepared in the previous step), 4,4-dimethylcyclohexen-1-yl boronic acid and Pd(PPh3)4 according to the procedure in Example 1, step (e). Mass Spectrum (ESI, m/z): Calcd. for C19H28N2O2, 317.2 (M+H). found 317.1.
Reaction SMILES: C(O[C:4](=[O:21])[CH:5]([N:7]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:8]1)[CH3:6])C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]2=[O:35])=[CH:25][C:24]=1[F:36]>>[F:36][C:24]1[CH:25]=[C:26]([N:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]2=[O:35])[CH:27]=[CH:28][C:23]=1[NH:22][C:4]([CH:5]([N:7]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:8]1)[CH3:6])=[O:21]
Reactant: CCOC(=O)C(C)N1CC[C@@H](NC(=O)c2ccc(Cl)s2)C1
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Product: CC(C(=O)Nc1ccc(-n2ccccc2=O)cc1F)N1CC[C@@H](NC(=O)c2ccc(Cl)s2)C1

Procedure:
6.4 Using general procedure F 2-{(R)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidin-1-yl}-propionic acid ethyl ester was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, prepared according to WO 2003045912) to give 5-chloro-thiophene-2-carboxylic acid ((R)-1-{1-[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-ethyl}-pyrrolidin-3-yl)-amide. Yellow solid. MS 487.4 ([M−H]−)
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][CH:6]([NH:24][C:25](=[O:38])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]=1.[OH-].[K+].C1COCC1>CO.O>[CH2:17]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH2:7][C@@H:6]([NH:24][C:25](=[O:38])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:5][CH2:4][C:3]([OH:39])=[O:2])=[CH:9]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CCC(Cc1cn(Cc2ccccc2)c2ccccc12)NC(=O)CCCCCCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CC[C@@H](Cc1cn(Cc2ccccc2)c2ccccc12)NC(=O)CCCCCCc1ccccc1
Reaction time: 0.67 h
Yield: 63.9 %

Procedure:
To a solution of 5-(1-benzyl-1H-indol-3-yl)-4-(7-phenyl-heptanoylamino)-pentanoic acid methyl ester (48 mg, 0.092 mmol) in MeOH (0.5 mL) was added KOH (100 mg, 1.79 mmol) in water (0.5 mL). THF (1 mL) was added to homogenise the solution and the reaction was complete in 40 min. The solvents were removed and water added. Upon washing with Et2O the aqueous layer was acidified with aqueous HCl and the resultant precipitate filtered. Upon drying the solid was recrystallised from THF/Et2O to afford the title compound (30 mg, 64%), mp 130.4-131.9° C. 13C NMR (DMSO-d6) δ 174.3, 171.8, 142.3, 138.4, 135.9, 128.4, 128.2, 128.2, 127.2, 127.1, 126.8, 125.5, 121.1, 118.9, 118.5, 111.3, 109.9, 48.9, 48.6, 35.5, 35.1, 30.9, 30.7, 30.5, 29.1, 28.5, 28.4, 25.2. ISMS: 511 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:24])[C:5]([C:18]2[N:19]=[N:20][N:21]([CH3:23])[N:22]=2)=[C:6]([C:8]2[CH:9]=[C:10]([F:17])[C:11]([C@H:14]([NH2:16])[CH3:15])=[N:12][CH:13]=2)[CH:7]=1.[F:25][C:26]1([F:35])[CH2:30][CH2:29][C:28]([OH:34])([C:31](O)=[O:32])[CH2:27]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([F:24])[C:5]([C:18]2[N:19]=[N:20][N:21]([CH3:23])[N:22]=2)=[C:6]([C:8]2[CH:9]=[C:10]([F:17])[C:11]([C@H:14]([NH:16][C:31]([C:28]3([OH:34])[CH2:29][CH2:30][C:26]([F:35])([F:25])[CH2:27]3)=[O:32])[CH3:15])=[N:12][CH:13]=2)[CH:7]=1
Reactant: C[C@@H](N)c1ncc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F
Reactant: O=C(O)C1(O)CCC(F)(F)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)C1(O)CCC(F)(F)C1)c1ncc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the compound of Reference Example 4 (0.766 g, 2.18 mmol), (+)-3,3-difluoro-1-hydroxycyclopentanecarboxylic acid (0.454 g, 2.73 mmol), (1H-1,2,3-benzotriazol-1-yloxy)-[tris(dimethylamino)]phosphonium hexafluorophosphate (1.35 g, 3.06 mmol) in anhydrous dichloromethane (43 mL), was added triethylamine (0.553 g, 5.46 mmol). This reaction mixture was allowed to stir at ambient temperature for 1 hour. After the reaction was judged complete by LC/MS analysis, the volume of the reaction was reduced in vacuo. The residue was taken up in EtOAc, washed with water, 0.25 N HCl and saturated aqueous sodium bicarbonate solution. The organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude residue was subjected to silica gel chromatography eluting with 0-50% EtOAc in hexanes to provide the title compound as a foam, which gave proton NMR spectra consistent with theory and a mass ion (ES+) of 499.2 for M+H+: 1H NMR (500 MHz, CDCl3) δ 8.13 (s, 1H), 7.96 (bd, NH), 7.34 (d, J=8.8 Hz, 1H), 7.26 (m, 2H), 5.41 (m, 1H), 4.342 (s, 3H), 2.82 (m, 1H), 2.46-2.25 (m, 4H), 1.92 (m, 1H), 1.45 (d, J=6.8 Hz, 3H).
Reaction SMILES: C(O[C:4](=[O:25])[NH:5][S:6]([C:9]1[CH:24]=[CH:23][C:12]2[CH2:13][CH2:14][N:15]([C:18](=[O:22])[N:19]([CH3:21])[CH3:20])[CH2:16][CH2:17][C:11]=2[CH:10]=1)(=[O:8])=[O:7])C.[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCOCC1>[CH:26]1([NH:31][C:4]([NH:5][S:6]([C:9]2[CH:24]=[CH:23][C:12]3[CH2:13][CH2:14][N:15]([C:18](=[O:22])[N:19]([CH3:21])[CH3:20])[CH2:16][CH2:17][C:11]=3[CH:10]=2)(=[O:8])=[O:7])=[O:25])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NC1CCCC1
Reactant: CCOC(=O)NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N(C)C)CC2
Solvent: C1COCCO1
Product: CN(C)C(=O)N1CCc2ccc(S(=O)(=O)NC(=O)NC3CCCC3)cc2CC1

Procedure:
A solution of 8.0 g. of [(3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]carbamic acid ethyl ester and 2.4 ml. of cyclopentylamine in 43 ml. of dioxane is heated under reflux for 1 hour and the solution subsequently evaporated in vacuo. Chromatography of the evaporation residue on 400 g. of silica gel with a mixture of 5 parts by volume of methanol and 95 parts by volume of chloroform yields the 1-cyclopentyl-3-[(3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]urea, m.p. 179°-180° C.
Reaction SMILES: [ClH:1].CS(N1CCNCC1)(=O)=O.C(O)(=O)C.O=C1CCN(C(OC(C)(C)C)=O)CC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+].[CH3:50][S:51]([N:54]1[CH2:59][CH2:58][N:57]([CH:60]2[CH2:65][CH2:64][N:63](C(OC(C)(C)C)=O)[CH2:62][CH2:61]2)[CH2:56][CH2:55]1)(=[O:53])=[O:52].Cl>ClCCCl.CO>[ClH:1].[ClH:1].[CH3:50][S:51]([N:54]1[CH2:55][CH2:56][N:57]([CH:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)[CH2:58][CH2:59]1)(=[O:52])=[O:53]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(S(C)(=O)=O)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CS(=O)(=O)N1CCNCC1
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)(=O)N1CCN(C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1-(methylsulfonyl)piperazine hydrochloride (150 g, 632 mmol) in DCE (3.5 L) was added TEA (192 g, 1.90 mol). The mixture was stirred at rt for 1 h and then acetic acid (94.8 g, 1.58 mol) and 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (251 g, 1.26 mol) was added. After stirring another h, the reaction was cooled with an ice water bath and NaBH(OAc)3 (294 g, 1.39 mol) was added in four portions. The mixture was stirred overnight at rt. The reaction mixture was neutralized with saturated Na2CO3 to pH 8-9. The organic phase was washed with brine and H2O, dried (Na2SO4), and rotovapped down to provide the crude Boc-protected amine (A combination of 3 batches, 720 g). This amount was split into 2 batches and used without further purification. To 1,1-dimethylethyl 4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinecarboxylate (360 g, 1.04 mol) in MeOH (1 L) was added HCl (6 M in MeOH, 2 L). The mixture was stirred at rt for 30 min. About 1 L of MeOH was rotovapped off. The resultant precipitate was filtered, washed with MeOH, and dried on high vacuum to provide the title compound of Step C (A combination of 2 batches, 600 g, 1.87 mol, 89% over 2 steps). 1H NMR (400 MHz, D2O) δ 1.87-1.91 (m, 2H), 2.33-2.36 (m, 2H), 2.97 (s, 3H), 2.99-3.05 (m, 2H), 3.45-3.59 (m, 11H).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].[CH3:12][Al](C)C.[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1.C1(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)C=CC=CC=1>[CH3:10][C:4]1[C:3]([CH3:11])=[C:2]([CH3:12])[C:7]([CH3:8])=[CH:6][N+:5]=1[O-:9]
Reactant: C[Al](C)C
Reactant: Cc1c[n+]([O-])c(C)c(C)c1Br
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1c[n+]([O-])c(C)c(C)c1C

Procedure:
4-Bromo-2,3,5-trimethyl-pyridine 1-oxide (2 g, 9.2 mmole) and catalytic tetrakis(triphenylphosphino)-palladium (80 mg, 4% by wt) in 20 mL of dry THF before treating with trimethylaluminum (2M in toluene, 15.2 mmole) under nitrogen. The solution was heated to reflux for 3 h, diluted with toluene (20 mL) before quenching the reaction with 4 mL of methanol followed by ammonium chloride (15 mmole). The mixture was refluxed for 2 h and filtered, while hot, on Celite. See J. Med. Chem. 1999, 42(12), 2064–2086. HPLC Rt: 4.183 min. 1H-NMR (CDCl3): δ 8.05 (s, 1H), 2.55 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.N1CCCCC1.[CH3:42][C:43]([N:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)([CH3:46])[CH:44]=O>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:42][C:43]([CH3:46])([N:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)[CH3:44])[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C=O)N1CCCCC1
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)N1CCCCC1
Yield: 7.7 %

Procedure:
A solution of 3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (150 .mg, 0.32 mmol), piperidine (0.03 mL, 0.32 mmol) and 2-methyl-2-(1-piperidyl)propanal (74.08 mg, 0.48 mmol) in ethanol (8 mL) was heated in a sealed tube at 90° C. for 16 hrs. The solution was cooled and concentrated. The residue was dissolved in ethyl acetate and washed with 5% citric acid and brine and then dried (MgSO4), filtered and concentrated. The crude material was purified by Isolera (10 grams column at 0% to 6% MeOH/ethyl acetate) to obtain 15 mg (8%) of the title compound. MS (pos. ion) m/z: 609 (M+1).