Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:34]3[C:29](=[N:30][CH:31]=[N:32][C:33]=3[NH2:35])[N:28]([C@H:36]3[CH2:41][CH2:40][C@H:39]([N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]4)[CH2:38][CH2:37]3)[N:27]=2)=[CH:22][C:21]=1[O:49][CH3:50]>ClCCl.CN(C=O)C.N1C=CC=CC=1>[NH2:35][C:33]1[N:32]=[CH:31][N:30]=[C:29]2[N:28]([C@H:36]3[CH2:41][CH2:40][C@H:39]([N:42]4[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]4)[CH2:38][CH2:37]3)[N:27]=[C:26]([C:23]3[CH:24]=[CH:25][C:20]([NH:19][C:6]([C:5]4[O:1][C:2]5[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=5[CH:4]=4)=[O:8])=[C:21]([O:49][CH3:50])[CH:22]=3)[C:34]=12
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2o1
Reaction time: 8 h

Procedure:
To benzo[b]furan-2-carboxylic acid (0.743 g, 4.58 mmol) in dichloromethane (14 mL) was added oxalyl chloride (4 mL, 45.8 mmol) and DMF (1 drop). The reaction mixture was stirred overnight. Solvent was evaporated and the residue was dissolved in Dichloromethane (5 mL). Half of the dichloromethane solution (2.5 mL) was added to a solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.50 g, 1.145 mmol) in pyridine (6 mL) at 0° C. After 30 minutes, the solid as collected by filtration. Water was then added to the solid and the pH of the solution was adjusted to 10 with sodium hydroxide (1.0N). The aqueous was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (80:20) as mobile phase to give trans-N2-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)benzo[b]furan-2-carboxamide (0.497 g, 75%). 1H NMR (DMSO-d6) δ 1.49 (m, 2H), 2.01 (m, 6H), 2.15 (s, 3H), 2.40 (m, 3H), 2.51 (m, 4H), 4.00 (s, 3H), 4.66 (m, 1H), 7.31 (m, 1H), 7.39 (m, 2H), 7.54 (m, 1H), 7.81 (m, 3H), 8.24 (m, 1H), 9.50 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][C@H:4]([OH:8])[CH2:5][CH:6]=[CH2:7].[CH2:9](Br)[CH:10]=[CH2:11]>CN(C)C=O>[CH2:11]([O:8][C@@H:4]([CH3:3])[CH2:5][CH:6]=[CH2:7])[CH:10]=[CH2:9]
Reactant: C=CCBr
Reactant: C=CC[C@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@@H](C)CC=C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (21 g, 34 mmol) in N,N-dimetylformamide (100 mL) was dropwise added (S)-pent-4-en-2-ol (10 g, 116 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. After that, allyl bromide (14.0 g, 116.2 mmol) was dropwise added to the mixture at 0° C. The resultant mixture was stirred at 0° C. for another 3 h, and the mixture was quenched by saturate ammonium chloride solution (500 mL). The aqueous layer was extracted with tert-butyl methyl ether (200 mL×3), and the combined organic layers were washed with water (100 mL×3) and brine (100 mL), dried over sodium sulfate, filtered and concentrated to afford (S)-4-(allyloxy)pent-1-ene (˜20 ml tert-butyl methyl ether solution), which was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].CN(C)C=O.[NH2:17][C:18]1[C:33]([Cl:34])=[CH:32][C:21]([C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][NH:28][CH2:27][C@H:26]2[OH:31])=[O:23])=[C:20]([O:35][CH3:36])[CH:19]=1>C(N(CC)CC)C>[NH2:17][C:18]1[C:33]([Cl:34])=[CH:32][C:21]([C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][C:5](=[O:6])[N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)[CH2:27][C@H:26]2[OH:31])=[O:23])=[C:20]([O:35][CH3:36])[CH:19]=1
Reactant: O=C(CCCCl)N1CCCC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@@H]1CCNC[C@H]1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@@H]1CCN(CCCC(=O)N2CCCC2)C[C@H]1O
Temperature: 70 °C
Reaction time: 18 h
Yield: 47.8 %

Procedure:
To a stirred solution of 3.00 parts of 1-(4-chloro-1-oxobutyl)pyrrolidine in 67.5 parts of N,N-dimethylformamide were added 1.93 parts of trans-4-amino-5-chloro-N-(3-hydroxy-4-piperidinyl)-2-methoxybenzamide and 1.5 parts of N,N-diethylethanamine and the whole was stirred for 18 hours at 70° C. The reaction mixture was evaporated and the residue was taken up in a sodium carbonate solution in water. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturate with ammonia, (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.1 parts (47.8%) of trans-4-amino-5-chloro-N-[3-hydroxy-1-[4-oxo-4(1-pyrrolidinyl)butyl]-4-piperidinyl]-2-methoxybenzamide; mp. 174.7° C. (compound 15).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].CON(C)[C:18]([C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH3:28])=[N:25][C:24]=2[CH:29]=1)=[O:19]>C1COCC1>[CH3:7][N:6]1[C:2]([C:18]([C:20]2[CH:21]=[CH:22][C:23]3[O:27][C:26]([CH3:28])=[N:25][C:24]=3[CH:29]=2)=[O:19])=[CH:3][N:4]=[CH:5]1
Reactant: Cn1cncc1Br
Reactant: CON(C)C(=O)c1ccc2oc(C)nc2c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc2cc(C(=O)c3cncn3C)ccc2o1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To a flask containing 5-bromo-1-methyl-1H-imidazole (700 mg, 4.35 mmol) was added THF (14 mL) and the solution was cooled to 0° C. To this clear homogeneous solution was added isopropylmagnesium chloride-LiCl complex (1.3 M in THF, 3.4 mL, 4.38 mmol) which resulted in a white suspension. The reaction was stirred at 0° C. for 25 min, then a THF solution (5 mL) of (N-methoxy-N,2-dimethylbenzo[d]oxazole-5-carboxamide (700 mg, 3.20 mmol, Intermediate 43, step a) was introduced and the mixture was allowed to warm to room temperature. The reaction was heated to 40° C. for 20 hours and then quenched with a saturated NH4Cl solution. The aqueous portion was extracted with EtOAc (4×50 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was triturated with DCM-Et2O (1:10) to afford the title compound as an amber solid. The mother liquors were concentrated and again triturated with Et2O to provide a second crop of the material. Finally, the mother liquors were concentrated and chromatographed on silica gel (10-50% acetone-DCM increasing gradient to 5% MeOH-DCM) to provide the title compound as a pale yellow solid.
Reaction SMILES: [N+]([C:4]([CH3:16])=[CH:5][C:6]1[S:7][CH:8]=[C:9]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:10]=1)([O-])=O.[OH2:17].Cl>[Fe].CO>[N:11]1([C:9]2[CH:10]=[C:6]([CH2:5][C:4](=[O:17])[CH3:16])[S:7][CH:8]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: CC(=Cc1cc(-n2ccnc2)cs1)[N+](=O)[O-]
Reactant: O
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: CC(=O)Cc1cc(-n2ccnc2)cs1

Procedure:
A mixture of 34 g (1-[2-(2-nitro-1-propenyl)-4-thienyl]-imidazole, 65 g iron powder, 0.9 ferrichloride hexahydrate, 51 ml methanol and 100 ml water are heated to reflux temperature while stirring. At this temperature, 65 ml concentrated hydrochloric acid are added dropwise within 1 hour. Subsequently, stirring is continued for 11/2 hours under reflux. After cooling, the mixture is stirred into 4 times the amount of methanol. Then, it is filtrated. The filtrate is evaporated to about 1/5 of its volume and filled up with water to 500 ml. The precipitated brown deposit is sucked off, then the filtrate is extracted several times with dichloromethane. The united dichloromethane phases are dried and evaporated. The residual crude product is used in the following reaction steps without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]C(=O)C)=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O>O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)c1ccc(N)c([N+](=O)[O-])c1

Procedure:
N-(4-acetyl-2-nitrophenyl)acetamide (26.5 g, 11,94 mmol) was added to a mixture of water and concentrated sulfuric acid, 150 ml (1:2). After 15 minutes the mixture was poured into water. The product was filtered off, washed with water and dried.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.[H-].[Na+]>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:7](=[O:10])[N:8]([CH2:26][C:27]2[CH:34]=[CH:33][C:30]([CH3:31])=[CH:29][CH:28]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(CBr)cc1
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCCc1nn(Cc2ccc(C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 76 %

Procedure:
The alkylation of 5-n-butyl-4-[(2'-cyanobiphenyl-4-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with 4-methylbenzyl bromide was carried out as described in Example 3, Step A, except that no excess sodium hydride was used. After work-up, flash chromatography of the crude product on silica gel (eluting with 0.6% methanol in CH2Cl2) provided a 76% yield of the title compound as a clear oil, homogeneous by TLC (98:2 CH2Cl2 --MeOH), mass spectrum (FAB) m/e 437 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.C[N:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][C:39]([NH2:45])=[CH:40][CH:41]=2)[CH2:36]1>CC(O)C.Cl>[NH2:35][CH:44]1[CH2:36][C:37]2[C:42](=[CH:41][CH:40]=[C:39]([NH:45][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=6[F:32])[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:38]=2)[CH2:43]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: CN1CCc2ccc(N)cc2C1
Agent: Cl
Solvent: CC(C)O
Product: NC1Cc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)c6c(F)cccc6F)c5)nn5ccccc45)n3)cc2C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a suspension of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (100 mg, 0.22 mmol) (prepared according to a procedure similar to that described in Example 27, Step C) and 2-methyl-1,2,3,4-tetrahydro-7-isoquinolinamine (44 mg, 0.27 mmol) in 2-propanol (3 mL) was added 2 drops of concentrated HCl. The mixture was stirred at 90° C. overnight, and the reaction mixture was partitioned between saturated aqueous NaHCO3 and 4:1 CHCl3/MeOH. The organic layer was dried over MgSO4, filtered, and purified by flash chromatography to give the title compound as a yellow oil (76 mg, 59% yield). 1H NMR (400 MHz, d6-DMSO): δ 10.95 (s, 1H), 9.44 (s, 1H), 8.85 (d, J=7.0 Hz, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.26 (d, J=5.3 Hz, 1H), 8.02 (s, 1H), 7.83 (d, J=9.2 Hz, 1H), 7.55-7.65 (m, 1H), 7.45-7.49 (m, 2H), 7.35-7.39 (m, 1H), 7.26 (t, J=8.1 Hz, 2H), 7.14 (t, J=6.8 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.52 (d, J=5.3 Hz, 1H), 6.35 (d, J=8.0 Hz, 1H), 6.21 (s, 1H), 3.30 (s, 2H) 2.75 (t, J=5.5 Hz, 2H), 2.52-2.63 (m, 2H), 2.26 (s, 3H). MS (ESI) m/z=588 [M+H]+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[C:11]2[C:12](=[O:24])[N:13]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][C:10]=2[NH:9][CH:8]=1.O.[OH-].[Na+].CN(C)[CH:30]=[O:31]>>[CH3:6][C:7]1[C:11]2[C:12](=[O:24])[N:13]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][C:10]=2[NH:9][C:8]=1[CH:30]=[O:31]
Reactant: Cc1c[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 31.7 %

Procedure:
A stirred solution of N,N-dimethylformamide (1.68 ml) was added dropwise slowly with phosphorus oxychloride (0.9 ml, 9.65 mmol) under an argon atmosphere while maintaining the temperature at 0° C. Upon completion of the addition, the mixture was stirred for 15 minutes at room temperature, and cooled down to 0˜5° C. in an ice-water bath. A mixture of 3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (2.29 g, 8.77 mmol) in 10.5 ml of N,N-dimethylformamide was added dropwise to the above solution. Upon completion of the addition, the mixture was stirred for 2 hours at 0° C., added with cold water (5 ml), stirred for 5 minutes. The resulting mixture was adjusted to pH 12 with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (30 ml×3). The combined organic extracts were washed with brine (15 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane:methanol (10:1) as eluents to give 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (989 mg, 3 steps 31.7%) as a red oil which was used as such.
Reaction SMILES: C(OC([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]([C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[N:24][C:25]([NH2:29])=[C:26]([OH:28])[CH:27]=3)=[CH:18][CH:17]=2)[CH2:10][CH:9]1[CH3:31])=O)(C)(C)C.Br[CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([F:44])([F:43])[F:42])[CH3:34].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[NH2:29][C:25]1[N:24]=[CH:23][C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:15]([N:11]3[CH2:10][CH:9]([CH3:31])[NH:8][CH:13]([CH3:14])[CH2:12]3)=[O:30])=[CH:21][CH:20]=2)=[CH:27][C:26]=1[O:28][CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([F:42])([F:43])[F:44])[CH3:34]
Reactant: CC1CN(C(=O)c2ccc(-c3cnc(N)c(O)c3)cc2)CC(C)N1C(=O)OC(C)(C)C
Reactant: CC(Br)c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CN(C(=O)c2ccc(-c3cnc(N)c(OC(C)c4ccccc4C(F)(F)F)c3)cc2)CC(C)N1
Temperature: 70 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
To a mixture of 4-[4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoyl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (50 mg, 0.12 mmol) and 1-(1-bromo-ethyl)-2-trifluoromethyl-benzene (32 mg, 0.12 mmol) in DMF (2 ml) was added 2 M Cs2CO3 (0.18 mL, 0.35 mmol), followed by water (0.5 mL), the mixture was stirred overnight then heated at 70° C. for 8 hr, LCMS showed that the reaction was completed. The DMF and water were removed. TFA (2 mL was added to the residue and stirred at room temperature for 3 hr. The TFA was removed, followed by addition of methanol. The residue was purified by prep-HPLC to afford (4-{6-amino-5-[1-(2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl)-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone (20 mg, yield 34.2%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[S:7][C:8]([C:12]2[CH:13]=[CH:14][C:15]([O:22][CH3:23])=[C:16]([S:18](Cl)(=[O:20])=[O:19])[CH:17]=2)=[C:9]([CH3:11])[N:10]=1)[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[NH3:31].O>O1CCOCC1>[CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[S:7][C:8]([C:12]2[CH:13]=[CH:14][C:15]([O:22][CH3:23])=[C:16]([S:18]([NH2:31])(=[O:20])=[O:19])[CH:17]=2)=[C:9]([CH3:11])[N:10]=1)[CH3:2]
Reactant: N
Reactant: CCNC(=O)Nc1nc(C)c(-c2ccc(OC)c(S(=O)(=O)Cl)c2)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1nc(C)c(-c2ccc(OC)c(S(N)(=O)=O)c2)s1
Reaction time: 2 h

Procedure:
To a stirred solution of 5-[2-(3-ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxy benzenesulfonylchloride (Example 28d) (0.2 g, 0.514 mmol) in dioxane (10 ml) is added 2 M Na2CO3 (0.515 ml) followed by 0.5 M NH3 in dioxane (2.06 ml). After 2 hours at room temperature, the reaction mixture is poured into water (200 ml) then extracted with ethyl acetate (3×50 ml). The combined organic layers are dried over MgSO4, filtered and concentrated to afford 5-[2-(3-ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxy-benzenesulfonamide as a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH:9]1[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([CH2:28][N+:29]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+]>>[C:28]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10]1)#[N:29]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)CC1CC(=O)CCN1C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CC(C)CC1CC(C#N)CCN1C(=O)OC(C)(C)C

Procedure:
The compound was prepared as described in Reference Compound 1, Step 1 from 2-Isobutyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.55 g, 17.8 mmol), toluene-4-sulfonylmethyl isocyanide (5.2 g, 26.7 mmol) and potassium tert-butoxide (53.4 mL, 1 M in tert-butanol) which yielded crude tert-butyl 4-cyano-2-isobutylpiperidine-1-carboxylate. MS m/z 267 (M+H)+.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]([CH:13]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=2)[CH2:14]1)=O.C([BH3-])#N.[Na+]>CO>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:13]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)[CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(CN2CCC(C=O)C2)cc1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.6 %

Procedure:
A solution of (1R,2S)-2-phenylcyclopropanamine (300 mg, 2.252 mmol) and methyl 4-((3-formylpyrrolidin-1-yl)methyl)benzoate (501 mg, 2.027 mmol) in methanol (50 mL) was heated to reflux for 5 minutes. The reaction mixture was cooled to room temperature and sodium cyanoborohydride (212 mg, 3.38 mmol) was added. The reaction was stirred at room temperature for 16 hours. After concentrating, dichloromethane was added and the solution was washed with water, dried over MgSO4, filtered and concentrated. HPLC purification (reverse phase) was performed with a Gemini NX 5u C18 110A, AXIA. 100×30.00 mm 5 micron column. A 7 minute gradient run (0% AcCN/H2O, 0.1% Formic Acid to 55% ACN/H2O, 0.1% Formic Acid) with UV detection at 214 nm was utilized. Added 1 ml of 1N HCl to fractions containing product and concentrated. Only the desired ester was seen by LC/MS of fractions before concentrating. Obtained 300 mg of a mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].CC1(C)[O:18][C:17](=O)[CH:16]=[C:15]([CH3:20])[O:14]1>>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:17](=[O:18])[CH2:16][C:15](=[O:14])[CH3:20])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: COC(=O)c1nccnc1N
Product: COC(=O)c1nccnc1NC(=O)CC(C)=O

Procedure:
3-Aminopyrazine-2-carboxylic acid methyl ester (12 g) and 2,2,6-trimethyl-[1,3]dioxin-4-one (15.6 ml) were heated to reflux for 6 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 4:1, then ethyl acetate) to give 3-(3-oxo-butyrylamino)-pyrazine-2-carboxylic acid methyl ester as a beige solid (15 g). 1H-NMR (400 MHz, CDCl3): 2.33 (s, 3H), 3.91 (s, 2H), 4.05 (s, 3H), 8.40 (d, 1H), 8.51 (d, 1H), 10.06 (s, 1H) ppm.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH:11]=O)[CH:4]=[CH:3][CH:2]=1.[C:13](=[O:20])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[NH2:14].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([O-])(=[O:29])=[O:28])=[CH:23][CH:22]=1.[Na+].Cl[Si](C)(C)C>C(#N)C.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH:11]([NH:14][C:13](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc2cccnc12
Reactant: CC(C)(C)OC(N)=O
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(S(=O)(=O)C(NC(=O)OC(C)(C)C)c2cccc3cccnc23)cc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
5.0 g (32 mmol) of 8-quinolinecarbaldehyde were added to a solution of 5.6 g (48 mmol) of tert-butyl carbamate and 8.5 g (48 mmol) of sodium p-toluenesulfonate in 112 ml of acetonitrile under argon. While cooling to 0-10° C., 6.9 g (64 mmol) of chlorotrimethylsilane were added dropwise, and the mixture was left to stir at room temperature overnight. After addition of 130 ml of water, the precipitated product was filtered off with suction and dried in vacuo at 50° C. 11.4 g of tert-butyl [quinolin-8-yl(toluene-4-sulfonyl)methyl]carbamate were obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([C:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH:8](Br)[C:7]=1O)=[O:5])[CH3:2].[CH2:17]([O:24][CH2:25][CH2:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([CH:6]1[C:7]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:26][CH2:25][O:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[CH2:9][CH:10]([CH3:12])[CH2:11]1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)C1=C(O)C(Br)CC(C)C1
Reactant: c1ccc(COCCNc2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Product: CCN(CC)C(=O)C1CC(C)Cc2c1c1ccccc1n2CCOCc1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 8 %

Procedure:
A mixture of 3-bromo-2-hydroxy-5-methyl-cyclohex-1-enecarboxylic acid diethylamide (47) (4.0 g, 14 mmol) and (2-benzyloxy-ethyl)-phenyl-amine (21; prepared according to Example 3(c)) (6.3 g, 28 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (14 mL) and dry zinc chloride (5.72 g, 42 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL) and washed with 2 N HCl (50 mL), water (2×50 mL) and aqueous potassium carbonate solution (2×50 mL) then dried and concentrated in vacuo. The crude mixture was purified by SCX cartridge (40 mL) and then silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (10-50% B, 100 g, 12 CV, 85 mL/min) to afford 467 mg (8%) of 9-(2-Benzyloxy-ethyl)-2-methyl-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (48) as a white solid. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δH 1.20-1.40 (9H, m, CH3 and N(CH2CH3)2), 1.90-2.20 (3H, m, 2-CH and 3-CH2), 2.35-2.45 (1H, m, 1-CH2), 2.85-2.95 (1H, m, 1-CH2), 3.40-3.70 (4H, m, N(CH2CH3)2), 3.70-3.80 (1H, m, 4-CH), 4.10-4.30 (4H, m, NCH2CH2OBn), 4.43 (2H, s, OCH2Ph), and 7.00-7.30 (9H, m, CHCHCHCH and Ph).