Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:47]1[CH:48]=[N:49][N:50]2[CH2:55][CH2:54][NH:53][CH2:52][C:51]=12.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:47]1[CH:48]=[N:49][N:50]2[CH2:55][CH2:54][N:53]([C:4]([C:3]3[CH:7]=[C:8]([CH2:11][C:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[O:22])[NH:14][N:13]=4)[CH:9]=[CH:10][C:2]=3[F:1])=[O:6])[CH2:52][C:51]=12
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: c1nc2n(n1)CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2ncnc2C1
Reaction time: 20 h
Yield: 21 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (360 mg, 1.20 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (600 mg, 1.80 mmol), 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine 16a (150 mg, 1.20 mmol, prepared according to a known method disclosed by “patent application WO2009090055”) and N,N-diisopropylethylamine (0.4 mL, 2.40 mmol). After stirring for 20 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-(6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 16 (100 mg, yield 21.0%) as a yellow solid.
Reaction SMILES: [NH:1]1[C@H:6]([C:7]([O-])=O)[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:10]([O-])=O.[C:13]1([NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19]>>[NH:19]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:20]=[C:7]1[C@H:6]1[NH:1][C@@H:2]([C:10]2[NH:20][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccccc1N
Reactant: O=C([O-])[C@@H]1CCC[C@H](C(=O)[O-])N1
Product: c1ccc2[nH]c([C@@H]3CCC[C@H](c4nc5ccccc5[nH]4)N3)nc2c1

Procedure:
2k was synthesised by an analogous procedure to that described for 2a using cis-2,6-piperidinedicarboxilate (1.4 g, 6.97 mmol) and o-phenylenediamine (1.51 g, 13.94). Yield 1.92 g (87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:26][C:27]([CH:29]2[CH2:31][CH2:30]2)=[O:28])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.[CH3:32][Si]([N-][Si](C)(C)C)(C)C.[K+].IC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:26]([CH3:32])[C:27]([CH:29]2[CH2:30][CH2:31]2)=[O:28])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: COc1cc(NC(=O)C2CC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(N(C)C(=O)C2CC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reaction time: 18 h
Yield: 58.4 %

Procedure:
To a solution of cyclopropanecarboxylic acid {3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amide (138 mg, 0.33 mmol) in DMF (2 mL) was added at ambient temperature potassium bis(trimethylsilyl)amide (0.91 M in THF, 0.44 mL, 0.40 mmol). After the dark brown solution was stirred for 15 min iodomethane (25 μL, 0.40 mmol) was added and the reaction mixture was stirred for 18 h in a closed flask. It was then extracted with water (20 mL) and ethyl acetate (20 mL). The combined organic layers were then washed with aqueous sodium carbonate (saturated, 20 mL), concentrated, dissolved in ethyl acetate (3 mL) and treated with heptane (3 mL). The resulting suspension was filtered off and washed with ethyl acetate:heptane 1:1 (3 mL) affording the title compound (83 mg, 58%) as a white solid. MS: m/e=431.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][C@@H:7]([CH3:10])[CH2:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:20]([S:23](Cl)(=[O:25])=[O:24])([CH3:22])[CH3:21]>C(Cl)Cl>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][C@@H:7]([CH3:10])[CH2:8][NH:9][S:23]([CH:20]([CH3:22])[CH3:21])(=[O:25])=[O:24])=[CH:4][CH:3]=1
Reactant: C[C@@H](CN)Oc1ccc(Br)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)NC[C@H](C)Oc1ccc(Br)cc1
Temperature: 0 °C

Procedure:
The above prepared (2S)-2-(4-bromophenoxy)propylamine was combined in a 500 mL 3-neck round bottomed flask with triethylamine (5.7 mL) and methylene chloride (110 mL), fitted with a thermometer, stirbar, and in a nitrogen system. The reaction mixture was cooled to 0° C. in an ice bath, with stirring, and isopropylsulfonyl chloride (2.75 mL, 24.585 mmol) was added by syringe. The mixture was stirred overnight, gradually becoming room temperature. The reaction was quenched with 100 mL water, and extracted two times with 100 mL methylene chloride. The organic extractions were combined, and washed with 200 mL brine, dried with sodium sulfate, filtered and concentrated in-vacuo, yielding 2.08 g viscous brown oil. This material was further purified using one Waters Prep-Pak® on a Waters Prep 2000 HPLC, in a 3:1 hexanes:ethyl acetate solvent system to provide the final title compound (1.63 g, 30%) as a viscous yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:10][CH:11]([F:23])[O:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>N1C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH:11]([F:10])[F:23])[CH:14]=2)(=[O:21])=[O:20])[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)F)c1
Reactant: Nc1cc(Br)cnc1Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)c1cccc(OC(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
To a 100 mL round-bottomed flask was added 3-amino-5-bromo-2-chloropyridine (855 mg, 4122 μmol), pyridine (5 ml), 3-(difluoromethoxy)benzenesulfonyl chloride (1000 μl, 4122 μmol). The reaction mixture was stirred at room temperature for overnight (ca 16 h). The solvent was removed in vacuo and the residue was dissolved in EtOAc (50 mL), washed with water (10 mL), saturated NaCl (10 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 20% EtOAc/hexanes to give N-(5-bromo-2-chloropyridin-3-yl)-3-(difluoromethoxy)benzenesulfonamide (566 mg, 33% yield) as a white solid. MS (ESI pos. ion) m/z calc'd for C12H8BrClF2N2O3S: 413.9. found 414.9. 1H NMR (300 MHz, chloroform-d) δ ppm 6.53 (t, J=72.27 Hz, 1H) 6.99 (s, 1H) 7.38 (dd, J=8.18, 1.75 Hz, 1H) 7.52 (t, J=8.04 Hz, 1H) 7.58 (s, 1H) 7.62-7.68 (m, J=1.17 Hz, 1H) 8.16 (d, J=2.34 Hz, 1H) 8.21 (d, J=2.19 Hz, 1H)
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]([S:8](/[N:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][C:25]3[C:24]4=[N:34][N:35]=[CH:36][N:23]4[CH:22]=[CH:21][C:20]=3[N:19]=2)=[CH:14][CH:13]=1)=[O:9])([CH3:7])[CH3:6]>C(Cl)Cl>[CH3:7][C:5]([S:8]([NH:10][CH:11]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:26][C:25]3[C:24]4=[N:34][N:35]=[CH:36][N:23]4[CH:22]=[CH:21][C:20]=3[N:19]=2)=[CH:16][CH:17]=1)[CH3:1])=[O:9])([CH3:4])[CH3:6]
Reactant: C[Mg]Br
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Solvent: ClCCl
Product: CC(NS(=O)C(C)(C)C)c1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methylmagnesium bromide solution (13.5 mL of 1.4 M solution in 3:1 toluene/THF, 19 mmol) was added to a stirred solution of 2-methyl-N-{(1E)-[4-(9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]methylidene}propane-2-sulfinamide (7-2, 298 mg, 0.66 mmol) in methylene chloride (5 mL) at −78° C. and the solution was warmed to rt. After 18 h, the reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated to give an amber foam, which was purified via silica gel chromatography (0-10% MeOH/CH2Cl2 over 30 min) to give the title compound as a yellow foam.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[NH2:23]>>[CH3:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[CH:3]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=3)[N:5]=[CH:6][N:7]=2)[CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: Cc1cc(C)cc(N)c1
Product: Cc1cc(C)cc(Nc2cc(Nc3ccc(P(C)(C)=O)cc3)ncn2)c1

Procedure:
The compound is prepared as in Example 59 by reacting 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine with 3,5-dimethylaniline.
Reaction SMILES: C([O:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][C:14]([CH3:29])([CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]([CH3:29])([CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:30][CH:31]=1
Reactant: CCOC(=O)C(C)(CCCc1ccccc1)Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Product: CCOC(=O)C(C)(CCCc1ccccc1)Cc1ccc(O)cc1
Yield: 107.2 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using ethyl 2-(4-benzyloxybenzyl)-2-methyl-5-phenylvalerate (1.88 g), which is the product of Reference example 7(c), and palladium on carbon (5%, 0.28 g) and the reaction mixture was treated to afford the desired compound (1.58 g) as a syrup.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9](S(C)(=O)=O)=[N:8][C:6]=2[N:7]=1.[CH3:21][S:22]([CH2:25][CH2:26][NH2:27])(=[O:24])=[O:23].C(N(CC)CC)C>>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[C:5]2[S:10][C:9]([NH:27][CH2:26][CH2:25][S:22]([CH3:21])(=[O:24])=[O:23])=[N:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)c1nc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CS(=O)(=O)CCN
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCNc1nc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
5-Chloro-2-(methylsulfonyl)-7-morpholinothiazolo[4,5-d]pyrimidine was reacted with 2-(methylsulfonyl)ethanamine (HCl salt), using 2.8 equiv of triethylamine, via General Procedure C, to give crude 5-chloro-N-(2-(methylsulfonyl)ethyl)-7-morpholinothiazolo[4,5-d]pyrimidin-2-amine, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure C again to give 133 after purification by reverse HPLC. MS (Q1) 437 (M+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:11]C(OCC)=O)[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[OH-].[K+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: CCOC(=O)Nc1cc(Br)cnc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(Br)cnc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of 5-bromo-3-(ethoxycarbonyl)amino-2-nitropyridine (1.57 g, 5.4 mmol) in ethanol (2.5 mL) was added KOH (813 mg, 14.5 mmol) in water (12.5 mL) and stirred at 90° C. for 1 hr then at room temperature for 1 hr. The mixture was added water. The formed precipitate was collected by filtration, washed with water then dried under reduced pressure to give the title compound (1.08 g, 92%): MS m/e 216, 218 (M−1).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.COC1C=CC(C[N:16]([C:35]2[CH:36]=[N:37][C:38]3[C:43]([CH:44]=2)=[CH:42][CH:41]=[C:40]([O:45]CC2C=CC=CC=2)[CH:39]=3)[C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=3)[CH:19]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:45][C:40]1[CH:39]=[C:38]2[C:43]([CH:44]=[C:35]([NH:16][C:17](=[O:34])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=4)[CH:19]=3)[CH:36]=[N:37]2)=[CH:42][CH:41]=1
Reactant: COc1ccc(CN(C(=O)c2ccc(OC)c(-c3cccc(OC)c3)c2)c2cnc3cc(OCc4ccccc4)ccc3c2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(-c2cc(C(=O)Nc3cnc4cc(O)ccc4c3)ccc2OC)c1
Yield: 42.5 %

Procedure:
Trifluoromethanesulfonic acid (120 μl, 204 mg, 1.36 mmol) was added to 32 (184 mg, 0.30 mmol) in 1:1 CH2Cl2:TFA (1.36 mL) and the solution was stirred at room temperature for 2 hours. The resulting solution was diluted with CH2Cl2 (100 mL), washed with saturated aqueous NaHCO3 (3×50 mL), saturated aqueous NaCl solution (2×50 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 100:1 EtOAc:MeOH to 4:1 EtOAc:MeOH) to give 34 as a yellow oil (51 mg, 43%): 1H NMR (CD3OD, 500 MHz) δ 9.01 (bs, 1H), 8.61 (bs, 1H), 8.02 (dd, J=8.5, 1.7 Hz, 1H), 7.97 (d, J=1.9 Hz, 1H), 7.74 (d, J=8.9 Hz, 1H), 7.30 (t, J=8.2 Hz, 1H), 7.27 (d, J=1.9 Hz, 1H), 7.19 (dd, J=8.9, 2.1 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 7.11-7.08 (m, 2H), 6.89 (m, 1H), 3.88 (s, 3H), 3.81 (s, 3H); 13C NMR (CD3OD, 125 MHz) δ 168.7, 161.2, 160.9, 160.2, 147.1, 146.2, 140.5, 132.0, 132.0, 131.5, 130.4, 130.2, 130.1, 128.5, 127.6, 124.2, 123.2, 121.5, 116.5, 113.8, 112.4, 109.7, 56.5, 55.9; IR (film) νmax 3281, 3203, 2930, 2835, 1605, 1545, 1499, 1371, 1252, 1036, 764, 735 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C24H20N2O4, 401.1501. found, 401.1481.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[CH3:2].CON(C)[C:19](=[O:31])[CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4](=[O:13])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=1[C:19](=[O:31])[CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:15]
Reactant: CCN(CC)C(=O)Oc1ccc(C)cc1
Reactant: CON(C)C(=O)CCCCOc1ccccc1
Product: CCN(CC)C(=O)Oc1ccc(C)cc1C(=O)CCCCOc1ccccc1

Procedure:
The title compound was prepared from 4-methylphenyl diethylcarbamate and N-methoxy-N-methyl-5-phenoxypentanamide following the same procedure used in Example F.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[CH3:15][O:16][CH2:17][C:18](Cl)=[O:19].O>C(Cl)Cl>[CH3:15][O:16][CH2:17][C:18]([NH:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][N:7]=1)=[O:19]
Reactant: NCc1nccs1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COCC(=O)NCc1nccs1
Reaction time: 0.25 h
Yield: 102 %

Procedure:
To a solution of 342 mg (3.0 mmol) of 2-aminomethylthiazole and 0.50 ml (3.6 mmol) of triethylamine in 5 ml of methylene chloride was added dropwise with ice-cooling a solution of 390 mg (3.6 mmol) of methoxyacetyl chloride in 2 ml of methylene chloride, and the mixture was stirred at the temperature for 15 minutes. To this was added 2 ml of water, and the mixture was stirred for 5 minutes. The organic layer was separated, and the aqueous layer was extracted two times with methylene chloride. The combined organic layers were washed with a small amount of a50% aqueous solution of potassium carbonate, dried over anhydrous potassium carbonate, and concentrated under reduced pressure. The residue was purified by flash column chromatography using silica gel, eluting with ethyl acetate to give 570 mg of the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([OH:15])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[CH3:39][NH:40][O:41][CH3:42].C(N(CC)CC)C>C(Cl)Cl>[CH3:42][O:41][N:40]([CH3:39])[C:13]([C@@H:10]1[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:9]1)=[O:15]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C

Procedure:
In a 500 mL round-bottomed flask under a positive pressure of nitrogen, was added a methylene chloride (125 mL) solution of (R)—N-Boc-pyrroldine-3-carboxylic acid (7.00 g, 0.0325 mol). This solution was cooled to 0° C. using an ice/water bath and treated sequentially with, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (7.48 g, 0.0390 mol) and 1-hydroxybenzotriazole (5.29 g, 0.0391 mol) in single portions. Following the addition of the coupling agents, the reaction mixture became cloudy, but upon further stirring a clear solution was obtained. The reaction mixture was stirred at 0° C. for 20 min then charged with N,O-dimethylhydroxylamine hydrochloride (4.78 g, 0.0490 mol) and triethylamine (13.5 mL, 0.0968 mol). The cooling bath was removed and the reaction mixture was allowed to warm to room temperature with stirring over a period of 1 h. The resulting solution was diluted with dichloromethane (600 mL) and 1 N HCl (1000 mL), mixed thoroughly and separated. The organic layer was washed with saturated aqueous sodium bicarbonate (300 mL) and saturated aqueous sodium chloride (300 mL), then dried over Na2SO4, filtered and concentrated to give tert-butyl (3R)-3-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate as a colorless oil (7.00 g; 83%). 1H NMR (400 MHz, CDCl3) δ 3.73 (s, 3H), 3.60-3.37 (m, 4H), 3.21 (s, 3H), 2.35-2.09 (m, 3H) 1.47 (s, 9H); ESI MS found for C12H22N2O4 m/z [159.1 (M+1-Boc)]
Reaction SMILES: [C:1]([C:3](=[C:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16](OCCC)=[O:17])=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:6]1=2)[CH3:4])#[N:2].[BH4-].[Li+].Cl>C1COCC1>[F:26][C:23]1[CH:24]=[CH:25][C:6]2=[C:7]([CH:22]=1)[O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][OH:17])[CH:13]=[CH:12][C:11]=1/[C:5]/2=[C:3](/[CH3:4])\[C:1]#[N:2]
Reactant: CCCOC(=O)c1ccc2c(c1)COc1cc(F)ccc1C2=C(C)C#N
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C/C(C#N)=C1/c2ccc(CO)cc2COc2cc(F)ccc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 46.5 %

Procedure:
[step 5] Propyl 11-(1-cyanoethylidene)-3-fluoro-6,11-dihydrodibenzo[b,e]oxepin-8-carboxylate (15.5 g, 44.1 mmol, E/Z=1/1) obtained in step 4 was dissolved in THF (220 mL), lithium borohydride (4.8 g, 221 mmol) was added, and the mixture was stirred at 60° C. for 3 hr. Under ice-cooling, the mixture was added dropwise to 2 mol/L hydrochloric acid, and the mixture was extracted 3 times with chloroform (550 mL). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified 3 times by silica gel column chromatography (hexane/ethyl acetate=100/0 v/v-40/60 v/v) to give (E)-2-[3-fluoro-8-(hydroxymethyl)dibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (6.06 g, 47%).
Reaction SMILES: NC1C=CC(C2N=C(N([CH2:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=O)=[CH:18][CH:17]=3)C)SC=2)=CC=1>O1CCCC1>[CH:15]1([C:16]2[CH:17]=[CH:18][C:19]([CH:20]=[O:22])=[CH:24][CH:25]=2)[CH2:24][CH2:25][CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)c1ccc(CN(C)c2nc(-c3ccc(N)cc3)cs2)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(C2CCCCC2)cc1
Yield: 260 %

Procedure:
Under an argon stream, tetrahydrofuran (1000 ml, 5.7 v/w) was added to methyl 4-(N-(4-(4-aminophenyl)-2-thiazolyl)-N-methylaminomethyl)benzoate (174.0 g, 0.493 mol) obtained in Example 1(4) and dissolved therein. A solution of 4-cyclohexylbenzaldehyde (120.6 g, 0.641 mol) obtained in Production Example 1(2) in tetrahydrofuran (740 ml, 4.3 v/w) was added. Acetic acid (56.4 ml, 0.986 mol) was added and the mixture was stirred at room temperature for 1 hr. With stirring under ice-cooling, sodium triacetoxyborohydride (104.5 g, 0.493 mol) was added and the mixture was stirred at room temperature for 1.5 hr. After ice-cooling, acetic acid (28.2 ml, 0.493 mol) and sodium triacetoxyborohydride (52.2 g, 0.246 mol) were added and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was ice-cooled and carefully added to a saturated aqueous sodium hydrogen carbonate solution (2262 ml, 13.0 v/w). After stirring at room temperature for 1 hr, the mixture was extracted with ethyl acetate (522 ml), and the organic layer was washed successively with distilled water (174 ml) and saturated brine (522 ml) and dried over magnesium sulfate (50.0 g). The solvent was evaporated and the obtained orange solid was purified by silica gel column chromatography (developing solvent chloroform:ethyl acetate=99.5:0.5) to give the title compound (80.3 g, yield 31.0%) as a pale-yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1.[ClH:24]>CO>[ClH:24].[CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C@H:9]([NH:15][C@H:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCCC3N[C@@H](C)c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1ccc2[nH]c3c(c2c1)CCC[C@H]3N[C@@H](C)c1ccccc1

Procedure:
(1R)-6-Methyl-N-[(1S)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt was prepared by separation of diastereomeric 6-methyl-N-[(1S)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine by SFC (Berger Amino, 10% methanol, 1500 psi, 40° C., 2 mL/min, retention time: 10.0 min.) The oil obtained was converted to the HCl salt to give a white solid. [α]25=22.5 (c 0.20, MeOH); 1H-NMR (DMSO-d6): δ 7.58 (d, J=7.6 Hz, 2H), 7.55-7.46 (m, 3H), 7.26 (d, J=8.0 Hz, 1H), 7.26 (m, 1H), 7.01 (d, J=8.8 Hz, 1H), 4.74 (q, J=7.2 Hz, 1H), 4.43 (t, J=4.8 Hz, 1H), 2.82 (dt, J=16.4 Hz, J=4.0 Hz, 1H), 2.68 (dt, J=16.4 Hz, J=4.8 Hz, 1H), 2.40 (s, 3H), 2.32-2.20 (m, 1H), 2.18-2.00 (m, 2H), 1.98-1.88 (m, 1H), 1.75 (d, J=6.8 Hz, 3H); MS m/z 184 (M−121).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].S(Cl)([Cl:24])(=O)=O>>[Cl:24][CH:14]([C:13](=[O:20])[CH2:12][N:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1=[O:1])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: O=S(=O)(Cl)Cl
Product: CCOC(=O)C(Cl)C(=O)CN1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared in a manner analogous to Intermediate 124 starting from ethyl 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-oxobutanoate (Intermediate 25) and sulfuryl chloride.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8]N(S(C)(=O)=O)C[CH2:5]1.[CH2:14]1C2(CNC2)[CH2:16][O:15]1>>[Cl:1][CH2:2][CH2:3][N:4]1[CH2:5][C:8]2([CH2:16][O:15][CH2:14]2)[CH2:9]1
Reactant: CS(=O)(=O)N1CCN(CCCl)CC1
Reactant: C1NCC12COC2
Product: ClCCN1CC2(COC2)C1

Procedure:
The title compound was prepared following the method described above for the synthesis of 1-(2-chloroethyl)-4-(methylsulfonyl)piperazine using 2-oxa-6-azaspiro[3.3]heptane as the starting reagent. The product was isolated as colorless oil (10 mg, 12%). LCMS: m/e 162.15 (M+H)+, 0.87 min (method 10).
Reaction SMILES: C(C1[CH:17]=[CH:16][C:6]2[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][O:9][C:5]=2[CH:4]=1)#N.[C:18]([OH:21])(=[O:20])[CH3:19].Cl>O>[C:10]1([C:7]2[C:6]3[CH:16]=[CH:17][C:19]([C:18]([OH:21])=[O:20])=[CH:4][C:5]=3[O:9][CH:8]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#Cc1ccc2c(-c3ccccc3)coc2c1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc2c(-c3ccccc3)coc2c1

Procedure:
A mixture of 54.7 g of 6-cyano-3-phenylbenzofuran, 200 ml of acetic acid and 100 ml of hydrochloric acid is heated to its reflux temperature and maintained at reflux for about 20 hours. An additional 100 ml of hydrochloric acid is added and the mixture is refluxed further for about 27 hours. The reaction mixture is then added to water and the aqueous solution is extracted with diethyl ether. The ether layer is extracted with dilute sodium hydroxide solution. The basic aqueous solution is acidified with 6N hydrochloric acid and the solid precipitate is collected by filtration. The solid is recrystallized from aqueous ethanol to provide 3-phenyl-6-benzofurancarboxylic acid, m.p. 160°-170° C.