Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:14](=[C:15]3[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]3)[CH:13]=[CH:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]2=1)[CH3:2].C1C2C=CC3C(=CC([CH:39]=[O:40])=C4C=3C=CC=C4)C=2C=CC=1>C(Cl)Cl>[CH2:1]([C:3]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:5](=[C:6]3[C:11](=[C:12]([CH:39]=[O:40])[CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7]3)[CH:4]=1)[CH3:2]
Reactant: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Reactant: CCc1cc2c3ccccc3ccc2c2ccccc12
Solvent: ClCCl
Product: CCc1cc2c3ccccc3c(C=O)cc2c2ccccc12
Yield: 76 %

Procedure:
6-Ethylchrysene (Cambridge Chemical, Inc., 60 g, 0.234 mol) was formylated according to the procedure outlined in 1A, except that CH2Cl2 (1 L) was used as the reaction solvent. The crude material was chromatographed on a plug of SiO2 (1 kg) using PhCH3 as the eluting solvent, afforded 50.38 g (76%) of 12-ethyl-6-chrysenecarbaldehyde mp 138°-139°, (C, H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.[ClH:19].[Cl:20][CH2:21][C:22]1[C:23]([N:33]([CH3:35])[CH3:34])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([CH3:32])=[CH:27][CH:26]=2>C1(C)C=CC=CC=1>[ClH:20].[ClH:19].[CH3:34][N:33]([CH3:35])[C:23]1[C:22]([CH2:21][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=2[OH:18])=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH3:32])[CH:29]=2)[N:24]=1
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: Cc1ccc2nc(N(C)C)c(CCl)cc2c1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCc1nc(O)c(Cc2cc3cc(C)ccc3nc2N(C)C)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 6.7 %

Procedure:
To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (173 mg, 0.638 mmol) in toluene (10 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added 3-(chloromethyl)-N,N,6-trimethylquinolin-2-amine hydrochloride RBO 35154 (158 mg, 0.638 mmol) and the mixture was stirred at 150° C. for 1.5 h. After cooling to RT, the volatiles were removed and the residue was taken back in CH2Cl2 (20 mL). This solution was washed with water (3×10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:7 N NH3 solution in MeOH=100:0 to 95:5) gave after evaporation 20.2 mg of 4-((2-(dimethylamino)-6-methylquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol as a yellow solid. The free base was dissolved in MeOH (2 mL) and converted into salt by addition of a 0.19 M HCl solution in MeOH (0.525 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-(2-dimethylamino-6-methyl-quinolin-3-ylmethyl)-6,7-dimethoxy-1-propyl-soquinolin-3-ol dihydrochloride 36 as a yellow solid (22.2 mg, 6.7% yield).
Reaction SMILES: CS(Cl)(=O)=O.[CH:6]1([NH:9][C:10](=[O:39])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@@H:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH2:35][CH2:36]O)[CH2:26][CH3:27])[C:19]3=[O:38])[CH:12]=2)[CH2:8][CH2:7]1.[CH2:40]([N:42](CC)[CH2:43][CH3:44])[CH3:41].O>ClCCl>[CH:6]1([NH:9][C:10](=[O:39])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@@H:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH2:35][CH2:36][N:42]4[CH2:43][CH2:44][CH2:41][CH2:40]4)[CH2:26][CH3:27])[C:19]3=[O:38])[CH:12]=2)[CH2:8][CH2:7]1
Reactant: CCN(CC)CC
Reactant: CC[C@@H](Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O)c1ccccc1OCCO
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC[C@@H](Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O)c1ccccc1OCCN1CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.21 mL) was added to a stirred solution of N-cyclopropyl-3-[3-[[(1R)-1-[2-(2-hydroxyethoxy)phenyl]propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide (410 mg) and triethylamine (0.5 mL) in dichloromethane (10 mL) at 0° C. The mixture was stirred for 1 h at 0° C. and 1 h at room temperature. Water was added and the organic phase was separated, (Na2SO4), filtered and concentrated in vacuo. The residue was treated with dichloromethane (10 mL) and pyrrolidine (0.73 mL) and the mixture was stirred at room temperature for 24 h. The mixture was concentrated in vacu. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound as a solid (147 mg).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=O)[O:17]C3C=CC=CC=3)=[CH:9][CH:8]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[N:40][CH:41]=1>>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([S:42]([NH:45][C:16]([NH:15][CH2:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([N:6]3[C:2]([CH3:1])=[C:3]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:4]([C:25]([F:26])([F:27])[F:28])=[N:5]3)=[CH:8][CH:9]=2)=[O:17])(=[O:43])=[O:44])=[N:40][CH:41]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cn1
Reactant: Cc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Product: Cc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(Cl)cn2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-{4-[5-methyl-4-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}ethylcarbamate (step 7 of Example 52) and 5-chloro-2-pyridinesulfonamide: MS (ESI) m/z 564 [M+H]+, 562 [M−H]−, 1H-NMR (CDCl3) δ 78.54 (1H, s), 7.96-7.90 (2H, m), 7.47-7.19 (7H, m), 6.91-6.79 (2H, m), 6.65 (1H, br.s) 5.98 (1H, br.s), 3.44 (2H, t, J=6.6 Hz), 2.83 (2H, t, J=6.7 Hz), 2.20 (3H, s).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5].[CH2:13]1COCC1.C[Mg]Br>O.CCOC(C)=O>[C:4]([CH:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1)(=[O:5])[CH3:13]
Reactant: CON(C)C(=O)C1CCOCC1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)C1CCOCC1
Reaction time: 6 h
Yield: 81 %

Procedure:
A flask was charged with N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide 2 (11.7 g, 67.5 mmol) and THF (350 mL). The resulting mixture was immersed in a cooling bath at −60° C., and methylmagnesium bromide (3.0 M in ether, 33.8 mL, 101.4 mmol) was added via syringe over ˜8 min. The temperature of the bath was allowed to rise to 0° C. over 6 h. At that time, the reaction was diluted with water and EtOAc and stirred vigorously for 10 min. The phases were separated, and the aqueous layer was extracted with EtOAc. The organic portions were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was subjected to column chromatography (120 g silica, 80 mL/min, 0% to 100% EtOAc/hexanes) to give 4-acetyltetrahydro-4H-pyran 3 (7.05 g, 55.0 mmol, 81%). 1H NMR (400 MHz, CDCl3) for 3: δ 3.95 (ddd, J=11.6, 4.4, 2.8 Hz, 2 H), 3.38 (dt, Jd=2.8 Hz, Jt=11.6 Hz, 2 H), 2.50 (m, 1 H), 2.12 (s, 3 H), 1.75 (m, 2 H), 1.65 (m, 2 H). LCMS for 3 (conditions D): tR=0.83 min, m/e=129.4 (M+H, base).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1.[Li+].CCC[CH2-].CN([CH:22]=[O:23])C>C1COCC1>[CH:22]([C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1)=[O:23]
Reactant: CC(=O)N[C@@H](C)c1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)c1ccc(C=O)cc1
Reaction time: 1 h

Procedure:
To 20.0 g (74.3 mmol) (S)—N-(1-(4-bromophenyl)ethyl)acetamid (WO 2012/01107) in 300 mL THF are added dropwise 75.0 mL (187 mmol)N-butyllithium (2.5 M in THF) at −78° C. and stirred for 1 h. 10.0 mL (124 mmol) DMF are added dropwise to the mixture at −78° C. and stirred for 2 h. After that aq. NH4CI solution is added and extracted with EtOAc. The organic layer is dried over Na2SO4, filtered and concentrated by evaporation. The residue is purified by column chromatography (silica gel, MeOH:DCM).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3=[CH:14][C:15]4[CH2:19][CH2:18][O:17][C:16]=4[CH:20]=[C:10]23)[C:2]1=[O:21].N1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.CC1C=CC(S(O[CH2:54][C@@H:55]2[CH2:60][O:59][CH2:58][CH2:57][O:56]2)(=O)=O)=CC=1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[O:56]1[CH2:57][CH2:58][O:59][CH2:60][C@H:55]1[CH2:54][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3=[CH:14][C:15]4[CH2:19][CH2:18][O:17][C:16]=4[CH:20]=[C:10]23)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCC3
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Product: O=C1N(C[C@@H]2COCCO2)c2ccccc2C12COc1cc3c(cc12)OCC3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and (S)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 1′-[(2R)-1,4-dioxan-2-ylmethyl]-6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (97%) as a colorless solid: mp 162-164° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ 7.302, 7.298 (ddd, J=7.8, 7.7, 1.3 Hz, 1H), 7.17-7.14 (m, 1H), 7.07-7.02 (m, 2H), 6.79 (s, 1H), 6.12, 6.09 (s, 1H), 4.91, 4.90 (d, J=8.9 Hz, 1H), 4.66, 4.65 (d, J=8.9 Hz, 1H), 4.48 (t, J=8.7 Hz, 2H), 3.98-3.78 (m, 4H), 3.75-3.55 (m, 4H), 3.45-3.37 (m, 1H), 3.14 (t, J=8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ177.9, 177.7, 155.1, 155.0, 154.92, 154.88, 142.8, 142.7, 132.3, 132.2, 128.94, 128.89, 128.84, 128.80, 127.8, 127.7, 123.9, 123.8, 123.5, 109.6, 109.4, 107.19, 107.16, 104.0, 103.9, 80.0, 79.9, 73.3, 71.7, 69.4, 69.2, 66.8, 66.7, 66.52, 66.48, 58.46, 58.43, 41.9, 41.8, 30.4; MS (ES+) m/z 380.0 (M+1).
Reaction SMILES: Cl.Cl.[CH:3]12[NH:10][CH:7]([CH2:8][CH2:9]1)[CH2:6][CH:5]([NH:11][C:12]([N:14]1[CH2:18][CH2:17][C@@H:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=3)[CH2:15]1)=[O:13])[CH2:4]2.CCN(C(C)C)C(C)C.[Si]([N:41]=[C:42]=[O:43])(C)(C)C>C(Cl)Cl>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([NH:19][C@@H:16]2[CH2:17][CH2:18][N:14]([C:12]([NH:11][CH:5]3[CH2:6][CH:7]4[N:10]([C:42]([NH2:41])=[O:43])[CH:3]([CH2:9][CH2:8]4)[CH2:4]3)=[O:13])[CH2:15]2)=[N:21][CH:22]=1)#[N:27]
Reactant: C[Si](C)(C)N=C=O
Reactant: N#Cc1ccc(N[C@@H]2CCN(C(=O)NC3CC4CCC(C3)N4)C2)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(N[C@@H]2CCN(C(=O)NC3CC4CCC(C3)N4C(N)=O)C2)nc1
Reaction time: 8 h

Procedure:
To a stirred solution of (3R)—N-(8-azabicyclo[3.2.1]octan-3-yl)-3-(5-cyanopyridin-2-ylamino)pyrrolidine-1-carboxamide dihydrochloride salt (17.5 mg, 0.042 mmol) and i-Pr2NEt (0.032 mL, 0.18 mmol) in CH2Cl2 (1 mL) was added Me3SiNCO (0.008 mL, 0.06 mmol). The mixture was stirred at overnight and concentrated. The residue was purified by prep HPLC to give two isomeric products.
Reaction SMILES: N1([C:6]([NH:8][C@:9]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C@H:10]2[CH:12]=[CH2:13])=[O:7])C=CN=C1.[Cl:19][C:20]1[C:21]([O:55][CH3:56])=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[C:27]([N:30]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[N:31]1)[CH:26]=[C:25]2[O:39][C@@H:40]1[CH2:44][NH:43][C@H:42]([C:45]([N:47]([CH2:49][CH2:50][CH2:51][CH2:52][CH:53]=[CH2:54])[CH3:48])=[O:46])[CH2:41]1.C(OC([C@@]1(NC(N2C[C@H](O)C[C@H]2C(=O)N(CCCCC=C)C)=O)C[C@@H]1C=C)=O)C>>[Cl:19][C:20]1[C:21]([O:55][CH3:56])=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[C:27]([N:30]1[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:37])[F:38])=[N:31]1)[CH:26]=[C:25]2[O:39][C@@H:40]1[CH2:44][N:43]([C:6]([NH:8][C@:9]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C@H:10]2[CH:12]=[CH2:13])=[O:7])[C@H:42]([C:45](=[O:46])[N:47]([CH2:49][CH2:50][CH2:51][CH2:52][CH:53]=[CH2:54])[CH3:48])[CH2:41]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)n1ccnc1)C(=O)OCC
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-n3ccc(C(F)(F)F)n3)nc3c(Cl)c(OC)ccc23)CN1
Agent: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)N[C@]1(C(=O)OCC)C[C@@H]1C=C
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-n3ccc(C(F)(F)F)n3)nc3c(Cl)c(OC)ccc23)CN1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C
Yield: 75 %

Procedure:
Compound 116 was synthesized from compounds 33 and 115 as a white solid in 75% yield, following the procedure as described for compound 50.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH3:17][O:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=O)[CH3:28])=[CH:23][CH:22]=1>O1CCCC1>[CH3:17][O:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24](/[C:27](/[CH3:28])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:23][CH:22]=1.[CH3:17][O:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24](/[C:27](/[CH3:28])=[CH:9]\[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:23][CH:22]=1
Reactant: COCOc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(/C)c1ccc(OCOC)cc1
Product: CCOC(=O)/C=C(\C)c1ccc(OCOC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.6 %
Yield: 42 %

Procedure:
9 ml of ethyl diethylphosphonoacetate was added dropwise to a suspension of 60% sodium hydride in oil (1.93 g) in 40 ml tetrahydrofuran and stirred at room temperature for 30 minutes. A solution of 4′-(methoxymethoxy)acetophenone (6.70 g) in 40 ml tetrahydrofuran was added dropwise to the reaction mixture, followed by stirring at room temperature for 17 hours and subsequently at reflux for 4 days. The solvent was evaporated, and the reaction mixture was mixed with water and then extracted with ethyl acetate. The resulting organic layer was washed with water and brine, and then dried over magnesium sulfate. The drying agent was filtered off and the solvent was evaporated to give a residue, which was then purified via column chromatography on silica gel (hexane:ethyl acetate=10:1) to provide ethyl (E)-3-[4-(methoxymethoxy)phenyl]-2-butenoate (3.91 g, 42%) as a colorless oil and ethyl (Z)-3-[4-(methoxymethoxy)phenyl]-2-butenoate (425 mg, 4.6%) as a colorless oil, respectively.
Reaction SMILES: CO[C:3]1[CH:4]([CH3:11])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[N:9]=1.[Cl-:12].[NH4+:13]>CO>[ClH:12].[CH3:11][CH:4]1[CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[NH:9][C:3]1=[NH:13]
Reactant: [Cl-]
Reactant: COC1=NC(C)CCCC1C
Reactant: [NH4+]
Solvent: CO
Product: CC1CCCC(C)C(=N)N1
Product: Cl
Yield: 102.4 %

Procedure:
The product of EXAMPLE 38 (1.24 g, 8.0 mmol) in 25 mL of MeOH was reacted with ammonium chloride (0.37 g, 6.8 mmol) by the method of EXAMPLE 27 to yield 1.23 g (91%) of the title material.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12]N)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].Cl.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>S(=O)(=O)(O)O.O1CCOCC1>[C:2]([C:6]1[CH:11]=[CH:10][C:9]2[NH:12][C:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][C:18]=3[C:8]=2[CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CN1CCC(=O)CC1
Reactant: CC(C)(C)c1ccc(NN)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CN1CCc2[nH]c3ccc(C(C)(C)C)cc3c2C1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
(4-tert-Butylphenyl)hydrazine hydrochloride (1 equiv.) is taken in 7% sulfuric acid in 1,4-dioxane. 1-Methylpiperidin-4-one hydrochloride (0.76-1.4 equiv.) is added and the contents are stirred at 80° C. for 3 h. The reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is concentrated and then quenched with aq. NaHCO3 solution, followed by extracted with EtOAc. The organic layer is dried over anhydrous sodium sulfate, evaporated to dryness and purified by column chromatography (5% MeOH-DCM) to afford 8-tert-butyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8](O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Br:11]P(Br)Br>C(OCC)C>[Br:11][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:9]
Reactant: BrP(Br)Br
Reactant: CC(O)c1cccc(Cl)c1
Solvent: CCOCC
Product: CC(Br)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of 1-(3-chlorophenyl)ethanol (0.2 g, 1.28 mmol) in diethyl ether (10 mL) at 0° C. was added tribromophosphine (0.38 g, 1.41 mmol). The mixture was warmed to room temperature and stirred overnight, then diluted with ether (10 mL). After quenching with water (10 mL), the organic phase was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel and eluted with petroleum ether to give the title compound as an oil (0.16 g, yield 57.1%).
Reaction SMILES: [CH2:1]=O.[C:3]1([C:8]([NH:10][C:11](=[O:19])[NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:9])[S:7][CH:6]=[CH:5][CH:4]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:1][N:16]2[CH2:17][CH2:18][CH:13]([NH:12][C:11]([NH:10][C:8](=[O:9])[C:3]3[S:7][CH:6]=[CH:5][CH:4]=3)=[O:19])[CH2:14][CH2:15]2)=[CH:21]1
Reactant: C=O
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(NC(=O)c1cccs1)NC1CCNCC1
Product: O=C(NC(=O)c1cccs1)NC1CCN(Cc2c[nH]c3ccccc23)CC1

Procedure:
Following the procedure of Example 1, formaldehyde, 4-(2-thenoyl)ureidopiperidine and indole are reacted together to obtain the title compound which is isolated as the hydrochloride mp 231°-232° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[CH:13]=[C:12]([CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([N+:26]([O-:28])=[O:27])=[CH:18][CH:17]=2)[CH:11]=[CH:10][N:9]=1.CCN(C(C)C)C(C)C.N>C(Cl)Cl.C1COCC1>[CH3:1][O:2][CH2:3][C:4]([NH:7][C:8]1[CH:13]=[C:12]([CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([N+:26]([O-:28])=[O:27])=[CH:18][CH:17]=2)[CH:11]=[CH:10][N:9]=1)=[O:5]
Reactant: COCC(=O)Cl
Reactant: Nc1cc(COc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Agent: N
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)Nc1cc(COc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.2 %

Procedure:
Methoxyacetyl chloride (24.2 mL, 264 mmol) was added dropwise over 10 min to a stirred suspension of the amine (3) (60.0 g, 203 mmol) in a mixture of DCM (300 mL), THF (450 mL) and DIPEA (53.1 mL, 305 mmol) under nitrogen at −5° C. After 10 min the reaction mixture was allowed to warm to RT during which time a dark solution formed. After 30 min a solution of NH3 (7M in MeOH, 30 mL) was added and stirring continued for 1 hr during which time a precipitate formed. The suspension was evaporated in vacuo and the residue was triturated with water (500 mL). The precipitate was collected by filtration, was washed with water (300 mL) and diethyl ether (500 mL) and then dried in vacuo at 60° C. to furnish the title compound (63) as a yellow solid (68 g, 88%): m/z 368 (M+H)+ (ES+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O.CN(C=O)C>C(Cl)Cl>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=C(O)c1ccccc1O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1O
Temperature: 60 °C

Procedure:
2-Hydroxy benzoic acid (1 g, 7.2 mmol) is dissolved in DCM (14 mL). To this mixture, thionyl chloride (1.57 mL, 22 mmol) and a catalytic amount of dry DMF are added. The resulting mixture is heated to 60° C. overnight, after which the resulting mixture is evaporated to give the desired product that is used as such.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:4]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[B]1OC2C(=CC=CC=2)O1>C1(C)C=CC=CC=1>[OH:26][C@@H:20]([C:3]1[C:2]([CH3:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[O:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:14])=[O:15])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(=O)c1c(C)cc2ccccc2c1OS(=O)(=O)C(F)(F)F
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: [B]1Oc2ccccc2O1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H](O)c1c(C)cc2ccccc2c1OS(=O)(=O)C(F)(F)F
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
Ethyl 2-(3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (1.31 g, 3.3 mmol) was dissolved in toluene (20 mL) and cooled to −40° C. After stirring for 20 minutes, (R)-(+)-2-Methyl-CBS-oxazaborolidine (219 mg, 7.5 mmol) and catecholborane (750 μL, 7.04 mmol) were added and the mixture stirred at −40° C. After 2 hrs at −40° C. the reaction was quenched by the addition of 15% Na2CO3 (12 mL) and the mixture was allowed to warm to room temperature. The mixture was washed with 15% Na2CO3 (8×12 mL) and saturated NH4Cl (24 mL), organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. Chromatography using silica gel using EtOAc in hexanes produced the desired (S)-ethyl 2-hydroxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate. 1H-NMR: 400 MHz, (CDCl3): δ 8.08-8.06 (m, 1H); 7.81-7.79 (m, 1H); 7.69 (s, 1H); 7.60-7.57 (m, 2H); 5.81-5.80 (m, 1H); 4.35-4.19 (m, 2H); 3.42 (d, J=2.4 Hz, 1H); 2.50 (s, 3H); 1.21 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40])[CH2:35][CH2:36][CH3:37].C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:43][CH2:42]1)=[O:40])[CH2:35][CH2:36][CH3:37]
Reactant: CCCCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)NC(=O)OC(C)(C)C)CC1
Reaction time: 12 h

Procedure:
To a solution of 1.61 g (S)-2-tert-Butoxycarbonylamino-5-(tert-butyl-diphenyl-silanyloxy)-pentanoic acid in 8 ml DMF were added 1.02 g piperazine-1-carboxylic acid butyl ester hydrotrifluoroacetate, 1.7 ml N-ethylmorpholine and 1.1 g TOTU. After stirring for 12 h the solution was diluted with ethyl acetate and subsequently washed with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 1.80 g.