Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=1I.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][N:13]=1.C(N(CC)CC)C.O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[C:19]#[C:18][C:15]1[CH:16]=[CH:17][C:12]([NH2:11])=[N:13][CH:14]=1
Reactant: CCc1nccc(Cl)c1I
Reactant: C#Cc1ccc(N)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nccc(Cl)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 1.0 g (3.7 mmol) 4-chloro-3-iodo-2-ethyl-pyridine and 485 mg (4.1 mmol) 2-amino-5-ethynyl-pyridine using 36 mg (0.40 mmol) CuI, 131 mg (0.40 mmol) PdCl2(PPh3)2 and 5.2 mL (39.5 mmol) triethylamine in 25 mL dry DMF. After completion of the reaction the reaction mixture is added dropwise into water. The precipitate is filtered off and taken up with iPrOH. The product remains is solution while the side-product (alkyne dimer from Glaser-homo-coupling) forms a precipitate and is filtered off. The mother liquid is concentrated under vacuum. Yield: 718 mg (75%).
Reaction SMILES: [O:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=[CH:2]1.[C:12]([C:15]1[CH:20]=[CH:19][C:18](F)=[C:17]([Cl:22])[CH:16]=1)(=[O:14])[NH2:13]>>[ClH:22].[C:12]([C:15]1[CH:20]=[CH:19][C:18]([O:11][CH:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]3[O:1][CH:2]=[CH:3][C:4]2=3)=[C:17]([Cl:22])[CH:16]=1)(=[O:14])[NH2:13]
Reactant: NC(=O)c1ccc(F)c(Cl)c1
Reactant: OC1CCNCc2occc21
Product: Cl
Product: NC(=O)c1ccc(OC2CCNCc3occc32)c(Cl)c1

Procedure:
The same method as in Example 3 was conducted using 5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 37) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-carbamoyl-2-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [Br:1][C:2]1[C:10]([Br:11])=[C:9]([Br:12])[CH:8]=[C:7]2[C:3]=1[C:4]([CH3:15])([CH3:14])[C:5]([CH3:13])=[N:6]2.[I:16][CH3:17]>>[I-:16].[Br:1][C:2]1[C:10]([Br:11])=[C:9]([Br:12])[CH:8]=[C:7]2[C:3]=1[C:4]([CH3:15])([CH3:14])[C:5]([CH3:13])=[N+:6]2[CH3:17]
Reactant: CI
Reactant: CC1=Nc2cc(Br)c(Br)c(Br)c2C1(C)C
Product: CC1=[N+](C)c2cc(Br)c(Br)c(Br)c2C1(C)C
Product: [I-]
Yield: 46.5 %

Procedure:
1.12 g (2.8 mmol) of 4,5,6-tribromo-2,3,3-trimethyl-3H-indole and 2 mL (32 mmol) of iodomethane were heated in a sealed tube at 30-35° C. for 24 hours. The formed precipitate was filtered, washed with small amounts of benzene and ether to yield 700 mg (47%) of 4,5,6-tribromo-1,2,3,3-tetramethyl-3H-indolium iodide. 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 8.50 (1H, s, arom.), 3.99 (3H, s, NCH3), 2.77 (3H, s, CH3), 1.60 (6H, s, C(CH3)2).
Reaction SMILES: [Br-].O[C@@H]1CCC[N+](CC(=O)NC2C=CON=2)(C)C1.[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1.[Br:27]CC(NC1C=CON=1)=O.Br[CH2:38][C:39]([NH:41][C:42]1[CH:47]=[N:46][CH:45]=[CH:44][N:43]=1)=[O:40]>>[Br-:27].[OH:26][CH:23]1[CH2:24][CH2:25][N+:20]([CH3:19])([CH2:38][C:39](=[O:40])[NH:41][C:42]2[CH:47]=[N:46][CH:45]=[CH:44][N:43]=2)[CH2:21][CH2:22]1
Reactant: O=C(CBr)Nc1ccon1
Reactant: O=C(CBr)Nc1cnccn1
Reactant: CN1CCC(O)CC1
Agent: C[N+]1(CC(=O)Nc2ccon2)CCC[C@@H](O)C1
Agent: [Br-]
Product: C[N+]1(CC(=O)Nc2cnccn2)CCC(O)CC1

Procedure:
This compound is prepared by an analogous method to (1R/S,3R)-3-Hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-methyl-piperidinium bromide (Intermediate C) by replacing (R)-1-methyl-piperidin-3-ol (step C3) with 1-methyl-piperidin-4-ol and by replacing 2-bromo-N-isoxazol-3-yl-acetamide (Intermediate A) with 2-bromo-N-pyrazin-2-yl-acetamide (Intermediate G).
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:30])[C:8]4[CH:20]=[C:19]([O:21][CH2:22][C@H:23]5[CH2:27][O:26]C(C)(C)[O:24]5)[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[Cu](C#N)[C:32]#[N:33].CC(N(C)C)=O>O>[OH:24][C@H:23]([CH2:27][OH:26])[CH2:22][O:21][C:19]1[CH:18]=[CH:17][C:9]2[C:10]([CH3:15])([CH3:16])[C:11]3[NH:12][C:13]4[C:5]([C:6]=3[C:7](=[O:30])[C:8]=2[CH:20]=1)=[CH:4][CH:3]=[C:2]([C:32]#[N:33])[CH:14]=4
Reactant: N#C[Cu]C#N
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)C(=O)c2c([nH]c4cc(Br)ccc24)C3(C)C)O1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC1(C)c2ccc(OC[C@H](O)CO)cc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Yield: 21.5 %

Procedure:
3-Bromo-9-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ3-1, 49.5 mg, 0.105 mmol) and copper cyanide (90%, 35.3 mg, 3.4 eq.) were added with DMA (0.5 mL), and the mixture was irradiated with microwave at 200° C. for 1 hr under nitrogen atmosphere. After cooling, the reaction solution was added with water and extracted with ethyl acetate. The insoluble matters were separated off by filtration, and the organic layer was washed with brine and dried over magnesium sulfate. After filtration and the concentration under reduced pressure, the resulting residues were purified by preparative TLC (methanol/dichloromethane) to obtain the title compound (white solid, 8.5 mg, 22%).
Reaction SMILES: [FH:1].[FH:2].[F:3][Si:4]([F:7])([F:6])[F:5].[NH3:8]>>[NH4+:8].[NH4+:8].[F:3][Si-2:4]([F:2])([F:1])([F:7])([F:6])[F:5]
Reactant: F[Si](F)(F)F
Reactant: N
Reactant: F
Product: [NH4+]

Procedure:
The method of claim 3 wherein the separately-recovered fluosilicic acid solution is reacted with ammonia to yield the ammonium fluosilicate solution of step (c).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:4]2[N:3]=1.C(N(CC)C(C)C)(C)C.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>CN1C(=O)CCC1>[O:50]1[CH2:51][CH2:52][N:47]([C:2]2[CH:7]=[C:6]([NH2:8])[N:5]3[N:25]=[CH:26][C:27]([C:28]4[CH:29]=[N:30][C:31]5[C:36]([CH:37]=4)=[CH:35][CH:34]=[CH:33][CH:32]=5)=[C:4]3[N:3]=2)[CH2:48][CH2:49]1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Nc1cc(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 200 °C

Procedure:
To a 2-5 mL microwave vessel is charged 5-chloro-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (72 μmol, 40 mg), N,N-diisopropylethylamine (220 μmol, 38 μL), NMP (2 mL), and morpholine (220 μmol, 19 μL). The reaction vessel is flushed with agron and sealed. The reaction mixture was heated to 200° C. in microwave synthesizer for 30 minutes. Upon completion, the NMP was removed in vacuo as an azeotropic using chlorobenzene. The crude product was purified via reverse-phase preparatory HPLC to yield 5-morpholino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine as brown-yellow solid. (m+H=347.31, retention time=2.97 min).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[CH3:8][N:9]([CH2:52][CH:53]=O)[C:10](=[O:51])[C:11]1[CH:50]=[CH:49][CH:48]=[C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][C:18]=2[C:29]2[CH:34]=[C:33]([C:35](=[O:47])[NH:36][C@@H:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:40][CH2:39][CH2:38]3)[CH:32]=[CH:31][N:30]=2)=[O:15])[CH:12]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>C(O)C>[CH3:8][N:9]([CH2:52][CH2:53][N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)[C:10](=[O:51])[C:11]1[CH:50]=[CH:49][CH:48]=[C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:19][C:18]=2[C:29]2[CH:34]=[C:33]([C:35](=[O:47])[NH:36][C@@H:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:40][CH2:39][CH2:38]3)[CH:32]=[CH:31][N:30]=2)=[O:15])[CH:12]=1
Reactant: O=C1CNCCN1
Reactant: CN(CC=O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CN(CCN1CCNC(=O)C1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
This compound was prepared according to the procedure described for the synthesis of Example 187 using piperazin-2-one in place of L-proline-tert-butyl ester. Into a 50-mL round-bottom flask, was placed a solution of (S)—N1-methyl-N1-(2-oxoethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide (100 mg, 0.16 mmol, 1.00 equiv) in ethanol (5 mL), piperazin-2-one (20 mg, 0.20 mmol, 1.20 equiv). This was followed by the addition of acetic acid (20 mg, 0.33 mmol, 2.20 equiv). The mixture was allowed to react with stirring for 1 h at room temperature. To this was added NaBH3CN (22 mg, 0.35 mmol, 2.20 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 7 with sodium bicarbonate (2 mol/L). The resulting solution was extracted with 3×20 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (20% CH3CN up to 40% in 6 min); Detector, Waters2545 UvDector 254&270 nm. 91.4 mg product was obtained. This resulted in 91.4 mg (54%) of (S)—N1-methyl-N1-(2-(3-oxopiperazin-1-yl)ethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide as a yellow solid. LCMS (ES, m/z): 714 [M+H]+ H-NMR (300 MHz, CD3OD, ppm): 8.94 (m, 1H), 8.70 (m, 1H), 8.40 (s, 2H), 8.12 (m, 3H), 7.85 (m, 1H), 7.72 (m, 3H), 7.17 (m, 3H), 5.39 (s, 1H), 3.94 (m, 3H), 3.56 (m, 7H), 3.09 (m, 3H), 2.86 (m, 3H), 1.95 (m, 8H).
Reaction SMILES: [Cl-:1].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:15][CH2:16][CH2:17][NH3+:18].Cl[C:20]1[CH:24]=[CH:23][S:22][C:21]=1[CH:25]=O>>[Cl:2][C:3]1[C:4]([O:15][CH2:16][CH2:17][NH:18][CH2:25][C:21]2[S:22][C:23]([Cl:1])=[CH:24][CH:20]=2)=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[CH:10][C:9]([C:13]#[N:14])=[CH:8]2
Reactant: [Cl-]
Reactant: O=Cc1sccc1Cl
Reactant: N#Cc1ccc2c(Cl)c(OCC[NH3+])ccc2c1
Product: N#Cc1ccc2c(Cl)c(OCCNCc3ccc(Cl)s3)ccc2c1
Yield: 63 %

Procedure:
Prepared from 2-[(1-chloro-6-cyanonaphthalen-2-yl)oxy]ethanaminium chloride and 5 chlorothiophen-2-carbaldehyde in 63% yield as a yellow solid.
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16](S(N4CCC(O)CC4)(=O)=O)=[CH:15][CH:14]=3)[N:11]=2)[CH2:4][CH2:3][CH2:2]1.NC1C=C2C(=CC=1)[N:39]([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:38](=[O:49])[CH2:37][CH2:36]2>>[CH:1]1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[C:17]4[C:16](=[CH:15][CH:14]=3)[N:39]([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:38](=[O:49])[CH2:37][CH2:36]4)[N:11]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1)N1CCC(O)CC1
Reactant: CCOC(=O)CN1C(=O)CCc2cc(N)ccc21
Product: CCOC(=O)CN1C(=O)CCc2cc(Nc3nc(NC4CCC4)c4cc[nH]c4n3)ccc21

Procedure:
According to the general procedure for synthesis of 1-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenylsulfonyl)piperidin-4-ol, ethyl 2-(6-amino-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate and 2-chloro-N-cylclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine gave Ethyl 2-(6-(4-(cyclobutyamino)-7H-pyrrolo[2,3-d]pyrimidine-2-ylamino)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate (MS calcd for C23H26N6O3 434.2. found [MH] 435.2; UV 209.8, 304.5 nm).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].Br[CH2:15][C:16]1[C:21]([F:22])=[CH:20][C:19]([C:23]2[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][C:17]=1[F:31]>O1CCCC1>[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:19]1[CH:18]=[C:17]([F:31])[C:16]([CH2:15][CH:3]([C:2](=[O:1])[CH2:8][CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH3:7])=[O:5])=[C:21]([F:22])[CH:20]=1)#[N:30]
Reactant: N#Cc1ccccc1-c1cc(F)c(CBr)c(F)c1
Reactant: CCCCC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(=O)C(Cc1c(F)cc(-c2ccccc2C#N)cc1F)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
A solution of methyl 3-oxoheptanoate (6 g) in tetrahydrofuran (50 mL) was added to a mixture of sodium hydride (1 g) and tetrahydrofuran (50 mL) at room temperature, and the mixture was stirred at room temperature for 30 min. And then, 4′-(bromomethyl)-3′,5′-difluorobiphenyl-2-carbonitrile (5.9 g) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated, the residue was extracted with 5% aqueous potassium hydrogensulfate solution and then with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless oil (7.2 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[CH:6][C:7]=1[CH:8]=[CH2:9].C(N(C(C)C)CC)(C)C.[CH3:20][Si:21]([CH3:38])([CH3:37])[CH2:22][CH2:23][O:24][C:25](ON1C2C=CC=CC=2N=N1)=[O:26]>CN(C)C=O.O>[CH3:20][Si:21]([CH3:38])([CH3:37])[CH2:22][CH2:23][O:24][C:25](=[O:26])[NH:10][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH2:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: C=Cc1ccc(N)cc1Cl
Reactant: C[Si](C)(C)CCOC(=O)On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=Cc1ccc(NC(=O)OCC[Si](C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3-chloro-4-vinyl-phenylamine (3.4 g) in N,N-dimethylformamide (44 mL) containing diisopropylethylamine (5.8 mL) is added 1-[2-(trimethylsilyl)-ethoxycarbonyl-oxy]benzotriazole (7.1 g) and the mixture is stirred at room temperature under an atmosphere of argon for three days. The solution is then diluted with water and extracted three times with diethyl ether. The combined organic extracts are washed successively with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue is chromatographed over silica gel (10% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH:20][CH2:19][CH2:18][CH2:17][N:8]2[CH:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Reactant: O=C=Nc1cccc(Cl)c1
Product: O=C(NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1)Nc1cccc(Cl)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 3-chlorophenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:60]1([C@H:66]([NH2:68])[CH3:67])[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:68][C@@H:66]([CH:60]3[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]3)[CH3:67])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: C[C@@H](N)C1CCCCC1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CC[C@H](C(=O)N[C@H](C)C2CCCCC2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.3 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then (1R)-1-cyclohexylethanamine (60.9 mg, 0.478 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water and dried to give the title compound (196 mg) as a yellow solid. LC-MS (ES) m/z=465 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].[F:8][CH2:9][C:10]([CH2:12][F:13])=O.C(OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[F:8][CH2:9][C:10]1([CH2:12][F:13])[O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2][O:1]1
Reactant: OCC(CO)CO
Reactant: O=C(CF)CF
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: COC(OC)OC
Product: OCC1COC(CF)(CF)OC1
Temperature: 60 °C
Reaction time: 10 h
Yield: 42.4 %

Procedure:
A mixture of 2-(hydroxymethyl)-1,3-propanediol (2.2 g, 20.7 mmol), 1,3-difluoroacetone (3.89 g, 41.4 mmol), trimethyl orthoformate (3.44 ml, 20.7 mmol), and p-toluenesulfonic acid monohydrate (356 mg, 2.07 mmol) was stirred at 60° C. for 10 hours. After completion of the reaction, triethylamine (577 μl) was added to the reaction mixture, which was then concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to obtain the title compound (1.6 g, yield: 43.4%) as a light yellow oil.
Reaction SMILES: Cl.[OH2:2].[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[F:10][C:11]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>C(Cl)Cl.C(N(CC)CC)C>[F:10][C:11]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:12]=1[C:13]([CH:6]1[CH2:7][CH2:8][NH:3][C:4](=[O:2])[CH2:5]1)=[O:14]
Reactant: O=C1CCNCC1
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CC(C(=O)c2ccc(F)cc2F)CCN1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.8 %

Procedure:
To a suspension of 4-piperidinone monohydrate hydrochloride (2.00 g, 13.28 mmol) in CH2Cl2 (40 mL) and triethylamine (5.0 mL) was added 2,4-difluorobenzoyl chloride (2.84 g, 15.93 mmol). The resulting mixture was stirred at room temperature for 5 hours before quenching with aqueous NaHCO3 (30 mL). Extracted with EtOAc (3×50 mL), dried (MgSO4), and concentrated to a residue which was purified by flash chromatography (EtOAc:Hexanes 9:1 to 1:1 ) afford product as an oil (2.25 g, 71%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][OH:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][O:25][S:34]([CH3:33])(=[O:36])=[O:35])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCO)c2cccc(F)c2)C1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCOS(C)(=O)=O)c2cccc(F)c2)C1
Temperature: 25 °C
Yield: 102.6 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(3-fluorophenyl)(2-hydroxyethoxy)methyl)piperidine-1-carboxylate (11 g, 31.16 mmol) in dry CH2Cl2 (140 mL) was added Et3N (12.60 g, 16.68 mL, 124.65 mmol, 4 eq) at −5-0° C. Then a solution of MsCl (7.1 g, 4.72 mL, 62.32 mmol, 2 eq) in dry CH2Cl2 (40 mL) was added dropwise at the same temperature. After addition, it was allowed to warm to rt gradually. Water (100 mL) was added. The aqueous layer was extracted with CH2Cl2 (3×80 mL), the combined organic layers was washed with 10% citric acid, sat. NaHCO3 and brine, then dried over Na2SO4, filtered and concentrated to give (R)-tert-butyl 3-((R)-(3-fluorophenyl)(2-(methylsulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (13.8 g), which was used in the next step without purification.
Reaction SMILES: [CH3:1]N(CCN(C)C)C.CC[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13].CN(CC)CC.[C:22]1([CH3:28])[CH:27]=CC=CC=1>>[CH:14]([N:11]([CH:22]([CH3:27])[CH3:28])[CH2:12][CH3:13])([CH3:15])[CH3:1]
Reactant: Cc1ccccc1
Reactant: CCN(CC)CC
Reactant: CN(C)CCN(C)C
Agent: CCN(C)CC
Product: CCN(C(C)C)C(C)C

Procedure:
Surprisingly, diisopropylethylamine in methylene chloride gave a 59:41 mixture of starting material:2-iodo product (Run #14), and only a trace of the 2-iodo product was observed in toluene under similar conditions. The low solubility of the hydrohalide salts of TMEDA, Et3N and Et2MeN in the above solvents may be responsible for their usefulness as opposed to the poor results with diisopropylethylamine. Precipitation of these hydrohalide salts may remove sufficient acid from the reaction so that the equilibrium is displaced toward product allowing the reaction to proceed to completion.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.C(N(CC)CC)C.C[Si]([CH:31]=[N+:32]=[N-:33])(C)C>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=[CH:14][CH:13]=[C:9]([C:10](=[O:12])[CH:31]=[N+:32]=[N-:33])[CH:8]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=CC(=O)c1cccc(-c2ccccc2)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 21 %

Procedure:
A mixture of 3-phenylbenzoic acid (595 mg, 3 mmol) and thionyl chloride (1 mL) was heated at 60° C. for 2.5 hours. After this time, the thionyl chloride was removed under vaccum. Toluene was then added and the resulting solution was concentrated. This procedure was repeated two more times. The oily residue was then dissolved in dry THF. At 0° C., triethylamine (304 μL, 3 mmol) and trimethylsilyldiazomethane were added successively. The reaction was then stirred for 20 hours at room temperature. The reaction was concentrated. Purification of the residue by flash chromatography using CH2Cl2/AcOEt 95:5 to 85:15 gave the compound as a yellow thick oil (141 mg, 21%). NMR 1H (ppm, CDCl3): 7.98 (t., J3=1.37 Hz, 1H), 7.74-7.67 (m, 2H), 7.60-7.57 (m, 2H), 7.50-7.24 (m, 4H), 5.95 (s, 1H). MS (+ESI): M+H+: 222.9.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9](OCCCC)(=O)[CH:10]=C>>[CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH2:10])=[CH2:1].[CH4:1]
Reactant: C=CC(=O)OCCCC
Reactant: C=Cc1ccccc1
Product: C
Product: C=Cc1ccccc1C=C

Procedure:
A polymerizable monomer consisting of 80.5 parts of styrene and 19.5 parts of n-butyl acrylate (Tg of the copolymer obtained by copolymerizing these monomers=55° C.), 0.3 part of polymethacrylic acid ester macromonomer (manufactured by Toagosei Co., Ltd.; trade name: AA6; Tg=94° C.), 0.5 part of divinyl benzene, 1.2 parts of t-dodecyl mercaptan, 7 parts of carbon black (manufactured by Mitsubishi Chemical Corporation; trade name: #25B) , and 7 parts of an antistatic resin (manufactured by Fujikura Kasei Co., Ltd.; trade name: FCA-626M were wet-ground using a media-type wet-grinding machine to prepare a polymerizable monomer composition for the core.