Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([OH:16])=[O:15])(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li+].[OH-].[CH3:22]O>>[CH3:22][O:15][C:14](=[O:16])[C@@H:13]1[CH2:17][CH2:18][CH2:19][N:12]1[S:9]([C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:10])=[O:11]
Reactant: CO
Reactant: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Yield: 90 %

Procedure:
To a solution of 24.8 g (0.15 mol) of L-Proline methyl ester hydrochloride in 500 mL of CH2Cl2 was added 70 mL (0.5 mol) of triethylamine with stirring to give copious white precipitate. The mixture was filtered, and the filtrate cooled to 0° C. (ice bath) with stirring. To the cooled solution was added a solution of 36.8 g (0.15 mol) of 3,5-dichlorobenzenesulfonyl chloride in 70 mL of CH2Cl2 dropwise quickly over five minutes. The addition funnel was rinsed with an additional 30 mL of CH2Cl2, and the cloudy yellow mixture was allowed to warm to room temperature with stirring overnight. The mixture was washed 2× with 400 mL of 1N HCl, 2× with 400 mL of 1N NaOH, then brine, then dried (MgSO4), filtered, and concentrated to a yellow oil which crystallized on standing. The material was recrystallized three times from ethyl acetate/hexanes to give 39.3 g (0.116 mol, 77%) of N-(3,5-dichlorobenzenesulfonyl)-Proline methyl ester (MW=338) as white needles (TLC on silica vs. 2:1 hexanes/ethyl acetate, Rf=0.51). M/z=339.3 (M+H+). N-(3,5-diChlorobenzenesulfonyl)-Proline: To a solution of 39.3 g (0.116 mol) of the above methyl ester in 250 mL methanol was added 115 mL (0.23 mol) of freshly-prepared 2M aqueous LiOH with stirring to give a colorless solution. This was stirred for three hours, after which HPLC showed no starting material. The solution was reduced by 50% in vacuo and partitioned between 1N HCl and CH2Cl2 (˜200 mL each). The phases were separated and the aqueous layer was washed again with CH2Cl2. The organic phases were combined, dried (MgSO4), and concentrated to a white, foamy solid. This was recrystallized twice from ethyl acetate/hexanes to give 33.8 g (0.104 mol, 90%) of the title compound as colorless, broad, flat needles. M/z=325.2 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[S:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH2:52][C:53](O)=[O:54].CCN(C(C)C)C(C)C>O.CN(C)C=O>[CH3:44][O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH2:52][C:53]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[S:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:54]
Reactant: Nc1nccc2scc(-c3ccc4c(c3)CCN4)c12
Reactant: COc1ccccc1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccccc1CC(=O)N1CCc2cc(-c3csc4ccnc(N)c34)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
To a 4 mL screw cap vial was added 3-(2,3-dihydro-1H-indol-5-yl)thieno[3,2-c]pyridin-4-amine (100 mg, 0.374 mmol) followed by HATU (142 mg, 0.374 mmol), 2-methoxyphenylacetic acid (62.2 mg, 0.374 mmol) and DIEA (0.261 mL, 1.496 mmol). N,N-Dimethylformamide (DMF) (2 mL) was added and the reaction was sealed and left to stir at room temperature overnight. The reaction mixture was poured into water (4 mL) and extracted with EtOAc (5 mL). The organics were dried over Na2SO4 and concentrated. The residue was taken up in DCM and purified via normal phase chromatography (0-10% MeOH/DCM). Fractions were collected and concentrated to afford 3-(1-{[2-(methyloxy)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)thieno[3,2-c]pyridin-4-amine (40.6 mg) as a white solid. LC/MS (ES) m/z=416.2 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 3.25 (t, 2H) 3.74-3.84 (m, 5H) 4.27 (t, 2H) 6.01 (br. s., 2H) 6.93 (t, 1H) 7.01 (d, J=7.83 Hz, 1H) 7.20 (dd, J=7.33, 1.52 Hz, 1H) 7.22-7.31 (m, 2H) 7.36 (s, 1H) 7.42 (d, J=6.06 Hz, 1H) 7.57 (s, 1H) 7.84 (d, J=6.06 Hz, 1H) 8.14 (d, J=8.08 Hz, 1H).
Reaction SMILES: O([C:8]([NH:10][C:11]1[CH:12]=[C:13]([N:17]2[C:21]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[S:28](=[O:31])(=[O:30])[CH2:29][C:20]=3[C:19]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:18]2)[CH:14]=[CH:15][CH:16]=1)=[O:9])C1C=CC=CC=1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(N(CC)CC)C>CN1CCCC1=O.O>[N:37]1([C:8]([NH:10][C:11]2[CH:12]=[C:13]([N:17]3[C:21]4[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=5[S:28](=[O:31])(=[O:30])[CH2:29][C:20]=4[C:19]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:18]3)[CH:14]=[CH:15][CH:16]=2)=[O:9])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1nn(-c2cccc(NC(=O)Oc3ccccc3)c2)c2c1CS(=O)(=O)c1ccccc1-2
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nn(-c2cccc(NC(=O)N3CCOCC3)c2)c2c1CS(=O)(=O)c1ccccc1-2
Temperature: 55 °C
Yield: 81.4 %

Procedure:
A mixture of ethyl 1-{3-[(phenoxycarbonyl)amino]phenyl}-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide (100 mg, 0.198 mmol), morpholine (0.03 mL, 0.3 mmol), triethylamine (0.03 mL, 0.3 mmol) in N-methyl-2-pyrrolidone is heated under microwave irradiation for 15 min at 55° C. The reaction mixture is diluted with water and is stirred for another hour. The precipitate is filtered and dried under vacuum to afford 80 mg (81%) of the title compound. MS (ESI+): 497.2.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5](Cl)[C:4]=1[N+:11]([O-:13])=[O:12].[CH3:14][O:15][CH2:16][CH2:17][NH2:18]>>[CH3:1][NH:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([NH:18][CH2:17][CH2:16][O:15][CH3:14])[C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: COCCN
Reactant: CNc1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Product: CNc1cc(Cl)cc(NCCOC)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
0.09 mole (20 g of 2-methylamino-4,6-dichloro nitrobenzene was added portionwise to 80 ml of 2-methoxyethyl amine preheated to 80° C. After 2 hours' heating, the reaction medium was diluted with 100 ml of ice water and the desired product precipitated out. After filtering, water washing then vacuum drying in the presence of P2O5, it was recrystallized from 96° ethanol. It melted at 93° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=C[CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C(OC=1C1C=CC=CC=1)=[N:42]C=CC=2>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:20])[C:30]4[C:35]([O:28][C:27]=3[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:42][CH:33]=[CH:32][CH:31]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=c1c(I)c(-c2ccccc2)oc2ncccc12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ncccc4c3=O)cc2)CCC1
Yield: 66 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-2-phenyl-pyrano[2,3-b]pyridin-4-one was reacted to give the title compound (46.7 mg, 66%) as a colourless gum. LCMS (Method A): RT=4.65 min, [M+Na]+=491.
Reaction SMILES: [OH-:1].[Ca+2:2].[OH-].[O-:4][P:5]([O:8]P([O-])([O-])=O)(=[O:7])[O-:6]>>[OH2:4].[OH2:1].[P:5]([O-:8])([O-:7])([O-:6])=[O:4].[Ca+2:2].[Ca+2:2]
Reactant: [OH-]
Reactant: O=P([O-])([O-])OP(=O)([O-])[O-]
Agent: [Ca+2]
Product: O
Product: O=P([O-])([O-])[O-]

Procedure:
adding to the solution additional amounts of the slaked lime slurry as well as a stabilizing amount of a pyrophosphate, to form a dicalcium phosphate dihydrate slurry having a pH ranging from about 4.9 to about 5.5, temperatures in steps 1 and 2 not to exceed about 40° C.;
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1.C([O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([Cl:28])[CH:22]=1)=[O:17])C>>[Cl:28][C:23]1[CH:22]=[C:21]([CH:19]2[CH2:20][CH:18]2[C:16]([OH:17])=[O:15])[CH:26]=[CH:25][C:24]=1[O:27][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(Cl)c1
Reactant: CC(C)Sc1cccc(CCl)n1
Product: CC(C)Sc1cccc(COc2ccc(C3CC3C(=O)O)cc2Cl)n1
Yield: 58.5 %

Procedure:
2-Chloromethyl-6-isopropylsulfanyl-pyridine (40 mg, 0.19 mmol) obtained in Step C of Preparation Example 16 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (52 mg, 0.21 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (42 mg, 65%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:8]Br)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)C.O.[C-:14]#[N:15].[Na+]>ClCCl>[Br:1][C:2]1[C:3]([CH2:8][C:14]#[N:15])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: BrCc1ncccc1Br
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: N#CCc1ncccc1Br
Reaction time: 0.5 h

Procedure:
The above pyridine (5.13 g, 20.4 mmol) was stirred in 50.1 mL of a 5.6:1 solution of ethanol:deionized water. To this mixture was added sodium cyanide (1.20 g, 24.5 mmol), which was stirred for 2 hours and 30 minutes. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (3×100 mL), and partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate, filtered, concentrated, and subjected to silica gel chromatography eluting with 5-30% EtOAc in hexanes to yield (3-bromopyridin-2-yl)acetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[N:14]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:17]1[CH:18]=[CH:13][N:14]=[C:15]([NH:19][CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[N:16]=1
Reactant: Cc1cc(F)cc2cc[nH]c12
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Cc1cc(F)cc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)c[nH]c12

Procedure:
The title compound was prepared as described in Example 215, starting from SEM-protected 5-Fluoro-7-methyl-1H-indole (prepared by Sugasawa synthesis starting from 4-fluoro-2-methyl-phenylamine, J. Med. Chem. 1990, 33, 2777) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by cleavage of the SEM protecting group with TBAF. Yield: 2.00 g (69%).
Reaction SMILES: [OH:1][C:2]1([C@H:6]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[NH:7][C:8]([NH:10][C:11]2[N:16]=[CH:15][C:14]3[C:17]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[N:18][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:13]=3[CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[OH:1][C:2]1([C@H:6]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:7][C:8]([NH:10][C:11]2[N:16]=[CH:15][C:14]3[C:17]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[N:18][NH:19][C:13]=3[CH:12]=2)=[O:9])[CH2:3][CH2:4][CH2:5]1
Reactant: COCCOc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@@H](c3ccccc3)C3(O)CCC3)ncc12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1n[nH]c2cc(NC(=O)N[C@@H](c3ccccc3)C3(O)CCC3)ncc12

Procedure:
In a manner similar to that described previously (e.g. Example 40, Step 3), (S)-1-((1-hydroxycyclobutyl)(phenyl)-methyl)-3-(3-(2-methoxyethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea was treated with TFA and triethylsilane in DCM. The product (102) was purified by Reverse phase C-18 HPLC (eluting with Acetonitrile/Water+0.1% TFA). MS: [M+H]+ m/z 412. 1H NMR (500 MHz, DMSO) δ 12.24 (s, 1H), 9.48 (s, 1H), 8.61 (s, 1H), 7.85 (bs, 1H), 7.38 (t, 2H, J=7.5 Hz), 7.36 (s, 1H), 7.27 (t, 2H, J=7.5 Hz), 7.20 (t, 2H, J=7.5 Hz), 4.78 (d, 1H, J=9 Hz), 4.42 (t, 2H, J=4.5 Hz), 3.70 (t, 2H, J=4.5 Hz), 3.30 (s, 3H), 2.12 (1H, m), 2.00 (m, 2H), 1.79 (m, 1H), 1.69 (m, 1H), 1.59 (m, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[Li]CCCC.[CH2:11](Cl)[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([O:12][CH2:11][N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1cn[nH]c1
Reactant: ClCOCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc(COCn2cccn2)cc1
Temperature: 25 °C

Procedure:
To a solution of pyrazole (4.92 g, 72.2 mmol) in THF (100 mL) at −78° C. is added n-BuLi (28.9 mL of 2.5M in hexane) dropwise. The mixture is warmed to RT then re-cooled to −78° C. then Bom-Cl (11.3 g, 72.2 mmol) is added and the mixture is allowed to warm to RT. The solvent is removed under reduced pressure and 1N NaOH (25 mL) is added to the residual solid. The mixture is extracted with ether and the organic phase is washed with brine and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue purified by reverse phase-MPLC using a gradient of 25-50% MeCN/water as eluent to give the title compound.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].Cl[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C(N(CC)CC)C>C(#N)C.CO>[CH3:2][N:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11]
Reactant: CNCCNC(=O)OC(C)(C)C
Reactant: Clc1ccccn1
Agent: Cl
Solvent: CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(CCNC(=O)OC(C)(C)C)c1ccccn1

Procedure:
A solution of tert-butyl [2-(methylamino)ethyl]carbamate hydrochloride (0.30 g, 0.0014 mol), 2-chloropyridine (160 mg, 0.0014 mol), and triethylamine (300 μL, 0.0021 mol) in acetonitrile (5 mL) was heated at 90° C. overnight. The mixture was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. Analytical LCMS: (M+H)+=252.1
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[C:24]([C:26]([N:28]2[C:36]3[C:31](=[CH:32][C:33]([F:37])=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)=[O:27])[CH:23]=[N:22][CH:21]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[F:37][C:33]1[CH:32]=[C:31]2[C:36](=[CH:35][CH:34]=1)[N:28]([C:26]([C:24]1[N:25]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:21]=[N:22][CH:23]=1)=[O:27])[CH2:29][CH2:30]2
Reactant: O=C(c1cncc(Cl)n1)N1CCc2cc(F)ccc21
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cncc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1)N1CCc2cc(F)ccc21

Procedure:
0.10 g (0.34 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one dihydrochloride, 0.11 g (0.34 mmol) (6-chloro-pyrazin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 0.20 mL (1.1 mmol) DIPEA were stirred in 1.0 mL DMF overnight at 80° C. 10 mL water were added to the reaction solution, the precipitate formed was suction filtered. The precipitate was stirred into methanol, suction filtered and dried.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([S:11][CH2:12][C:13]#[N:14])[N:3]=1.[CH2:15]([NH2:25])[C:16]1[CH:24]=[CH:23][C:22]2[O:21][CH2:20][O:19][C:18]=2[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[O:21]1[C:22]2[CH:23]=[CH:24][C:16]([CH2:15][NH:25][C:2]3[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([S:11][CH2:12][C:13]#[N:14])[N:3]=3)=[CH:17][C:18]=2[O:19][CH2:20]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CCCc1cc(Cl)nc(SCC#N)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCc1cc(NCc2ccc3c(c2)OCO3)nc(SCC#N)n1

Procedure:
A stirred suspension of 13.50 g. (0.06 mole) of (4-chloro-6-propyl-2-pyrimidinylthio)acetonitrile, 9.00 g. (0.06 mole) of piperonylamine and 6.36 g. (0.06 mole) of sodium carbonate was heated under reflux for six hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was dissolved in ethyl acetate, diluted with petroleum ether and was cooled in ice. The precipitate which formed was collected and recrystallized from a mixture of ethanol-petroleum ether to give 3.0 g. of product, m.p. 92°-94°.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[C:41]([CH3:43])[N:40]([CH2:44][CH3:45])[C:39](=[O:46])[CH:38]=1>>[CH2:44]([N:40]1[C:41]([CH3:43])=[CH:42][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[CH:38][C:39]1=[O:46])[CH3:45]
Reactant: CCn1c(C)cc(Br)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: CCn1c(C)cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-1-ethyl-6-methylpyridin-2(1H)-one following a procedure analogous to that described in Example 459 Step 4. LC-MS Method 2 tR=1.211 min, m/z=489.2; 1H NMR (CDCl3) 1.10 (s, 3H), 1.17 (s, 3H), 1.49 (s, 9H), 1.57 (d, 3H), 2.22 (m, 4H), 2.37 (m, 1H), 2.84 (m, 1H), 5.60 (m, 1H), 5.91 (s, 1H), 7.06 (d, 2H), 7.27-7.40 (m, 5H), 7.68 (d, 1H), 7.24 (d, 2H), 8.09 (d, 1H), 8.90 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.COC(OC)CCCNC.ClC1C=[C:23]2[C:27](=CC=1)NC=[C:24]2[CH2:30][CH2:31][NH:32][CH3:33].C=O>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][C:23]1[CH2:27][N:32]([CH3:33])[CH2:31][CH2:30][C:24]2=1
Reactant: CNCCc1c[nH]c2ccc(Cl)cc12
Reactant: NNc1ccc(Cl)cc1
Agent: C=O
Agent: CNCCCC(OC)OC
Product: CN1CCc2c([nH]c3ccc(Cl)cc23)C1

Procedure:
Method for the synthesis of compound 6 [6-chloro-2-methyl-9-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole]: (4-chlorophenyl)hydrazine is reacted with 4,4-dimethoxy-N-methylbutan-1-amine (Phytochemistry 1985, 24 (8), 1653-1656) to generate 2-(5-chloro-1H-indol-3-yl)-N-methylethanamine which upon treatment with formaldehyde, under standard Pictet Spingler reaction conditions (U.S. Pat. No. 2,642,438) gives 6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. The further reaction of this unsubstituted β-carboline with 2-(trifluoromethyl)-5-vinylpyridine gives the desired compound [6-chloro-2-methyl-9-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole], compound 6. After the successful synthesis of the compound, purification can be achieved using standard normal phase or reverse phase methods.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[CH2:26][C:27](O)=[O:28].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[CH2:26][C:27]([N:12]1[CH2:13][CH2:14][CH2:15][C:16]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[CH:10][C:11]1=2)=[O:28]
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cc1nc2ccccc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1nc2ccccc2o1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.023 g, 0.11 mmol), benzooxazol-2-yl-acetic acid (0.023 g, 0.13 mmol) and NEt3 (0.060 mL, 0.43 mmol) in DMF (0.6 mL) was added HATU (0.050 g, 0.13 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water. The mixture was partitioned between IPA/CHCl3 (1:2, 50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to afford the desired product (0.022 g, 53%). 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.71 (m, 1H), 7.53 (m, 1H), 7.45 (dd, J=8.8, 4.8 Hz, 2H), 7.34 (m, 2H), 7.15 (dd, J=8.8, 8.4 Hz, 2H), 4.25 (s, 2H), 3.88 (m, 2H), 2.83 (t, J=6.4 Hz, 2H), 2.08 (m, 2H); MS: (ES) m/z calculated for C21H17FN4O2 [M+H]+ 377.1, found 377.1.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[N-]=C=O.C1(CC2C=CC=CC=2)C=CC=CC=1.[C:20]([O-])(=[O:32])[CH2:21]CCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[C:57]([O:62]CCO)(=[O:61])[C:58]([CH3:60])=[CH2:59]>>[C:57]([OH:62])(=[O:61])[C:58]([CH3:60])=[CH2:59].[NH2:1][C:2]([O:32][CH2:20][CH3:21])=[O:3]
Reactant: [N-]=C=O
Reactant: C=C(C)C(=O)OCCO
Reactant: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: c1ccc(Cc2ccccc2)cc1
Product: C=C(C)C(=O)O
Product: CCOC(N)=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
In a 3 L four-necked flask equipped with a stirrer, a reflux condenser tube, a gas introducing pipe, and a thermometer, 500 g of diphenylmethane diisocyanate, 700 g of Actcol P-22 (polyether polyol manufactured by MITSUI TAKEDA CHEMICAL, INC.: weight average molecular weight=1,000), 300 g of Kuraray polyol C-1090 (carbonate polyester polyol manufactured by Kuraray Co., Ltd.: weight average molecular weight=1,000), and 0.2 g of dibutyltin dilaurate were placed. The mixture was reacted while being stirred at 60° C. for 4 hours. Subsequently, the reactant was stirred while 260 g of 2-hydroxyethyl methacrylate was added dropwise over 2 hours. After the completion of the dropwise addition, the resultant was reacted by stirring for 5 hours to obtain urethane methacrylate. Subsequently, to the urethane methacrylate, 754 g of styrene monomer was added to obtain a urethane methacrylate resin (U-7). The weight average molecular weight of the urethane methacrylate resin (U-7) was 6,473.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([C:12]1([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]#[N:32])=[CH:21][CH:20]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:42](Cl)(=[O:47])[CH2:43][CH2:44][CH2:45][CH3:46].N>C(OCC)(=O)C>[CH2:2]([O:9][C:10]([C:12]1([N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]#[N:32])=[CH:23][CH:24]=2)[C:42](=[O:47])[CH2:43][CH2:44][CH2:45][CH3:46])[CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCC(=O)Cl
Reactant: N#Cc1ccccc1-c1ccc(CNC2(C(=O)OCc3ccccc3)CCCC2)cc1
Agent: Cl
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)C1(C(=O)OCc2ccccc2)CCCC1
Reaction time: 15 h

Procedure:
A solution of 2.9 g (6.5 mmol) of N-(1-benzyloxycarbonylcyclopentyl)-N-(2'-cyano-biphenyl-4-ylmethyl)-amine hydrochloride and 4.4 ml (26 mmol) of Hunig base in 50 ml of ethyl acetate is treated with 1.1 g (9 mmol) of pentanoyl chloride, and the mixture is stirred for 15 hours at 25°-30°. After the addition of a further 0.5 g of pentanoyl chloride the mixture is stirred for a further 8 hours. The reaction mixture is then treated with 10 ml of aqueous ammonia solution (5%) and stirred for 0,5 hours. The ethyl acetate phase is separated, washed in succession with 2 N-hydrochloric acid, water and sodium hydrogencarbonate solution, dried and evaporated. The N-(1-benzyloxycarbonylcyclopentyl)-N-(2'-cyanobiphenyl-4-ylmethyl)-N-pentanoyl-amine is thus obtained in the form of a brown oil [Rf : 0.53 (system B7)], which is used for further reactions in crude form.