Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:11]3[CH2:26][CH2:25][CH2:24][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21]([OH:23])=O)[N:15]=2)[CH:5]=1)([CH3:3])[CH3:2].Cl.[CH3:28][NH:29][CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:11]3[CH2:26][CH2:25][CH2:24][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[C:21]([N:29]([CH3:30])[CH3:28])=[O:23])[N:15]=2)[CH:5]=1)([CH3:2])[CH3:3]
Reactant: CNC
Reactant: CC(C)c1cc(Nc2nc(N3CCCC3C(=O)O)nc3c2CCC3)n[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(Nc2nc(N3CCC[C@@H]3C(=O)N(C)C)nc3c2CCC3)n[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylic acid (300 mg, 0.842 mmol) in DMF (5 mL) was added dimethyl amine hydrochloride (343 mg, 4.213 mmol), HATU (320 mg, 0.842 mmol), diisopropylethylamine (163 mg, 1.263 mmol) and the reaction mixture was stirred at RT for 16 h. The progress of reaction was monitored by LCMS. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×30 mL). The organic layer was washed with water (8×40 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave a crude product which was purified by reverse phase HPLC followed by chiral HPLC to afford (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N,N-dimethylpyrrolidine-2-carboxamide, and its (S) enantiomer. 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 1.28 (d, 6H), 1.90-2.18 (m, 5H), 2.30-2.42 (m, 1H), 2.62-3.08 (m, 4H), 2.76 (s, 3H), 2.82-2.30 (m, 1H), 2.98 (s, 3H), 3.61-3.91 (m, 2H), 5.01 (d, 1H), 6.00 (brs, 1H).
Reaction SMILES: [O:1]1[C:6]2=[CH:7][C:8]3[C:9](=[O:15])[C:10](=[O:14])[NH:11][C:12]=3[CH:13]=[C:5]2[O:4][CH2:3][CH2:2]1.Br[C:17]1C=CC=C2C=1C(=O)C(=O)N2>>[CH3:17][N:11]1[C:12]2[CH:13]=[C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]3=[CH:7][C:8]=2[C:9](=[O:15])[C:10]1=[O:14]
Reactant: O=C1Nc2cc3c(cc2C1=O)OCCO3
Reactant: O=C1Nc2cccc(Br)c2C1=O
Product: CN1C(=O)C(=O)c2cc3c(cc21)OCCO3

Procedure:
Following the procedure as described in PREPARATION 79A, and making non-critical variations using 2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione to replace 4-bromoisatin, 6-methyl-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione was obtained (68%): 1H NMR (300 MHz, CDCl3) δ 7.09 (s, 1H), 6.74 (s, 1H), 4.41-4.38 (m, 2H), 4.27-4.24 (m, 2H), 3.08 (s, 3H); 13C NMR (75 MHz, CDCl3) δ; MS (ES+) m/z 220.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[N:4]=1.C(N(CC)CC)C.[CH3:41][N:42]([CH3:47])[S:43](Cl)(=[O:45])=[O:44]>C1(C)C=CC=CC=1>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:43]([N:42]([CH3:47])[CH3:41])(=[O:45])=[O:44])[CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[N:4]=1
Reactant: Nc1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)Nc1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Temperature: 70 °C
Reaction time: 22 h
Yield: 36.7 %

Procedure:
To a stirred solution of 3′-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-ylamine (example 220) (0.23 g, 0.5 mmol) in toluene (5 mL) was added triethylamine (0.21 mL) and dimethylsulfamoyl chloride (0.14 g, 1.0 mmol), the reaction mixture was allowed to stir at 70° C. for 22 h, poured into ice-water (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (EtOH/hexane) yielded the title compound (0.104 g, 37%) as an off-white solid. MS (ISP) 567.3 [(M+H)+]; mp 113° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18].C[Si](Cl)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1S
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: Brc1ccc(-c2nc3ccccc3s2)cc1
Temperature: 90 °C
Yield: 42 %

Procedure:
A mixture of 4-bromobenzoyl chloride (3.0 g, 24 mmol), 2-aminobenzenethiol (4.44 g, 24 mmol) and TMSCl (6.52 g, 60 mmol) in DMF (45 mL) was heated at about 90° C. overnight under argon. The mixture was poured into ice (300 g), and the whole was sonicated for about 20 min and yellow precipitate formed. After filtration, the solid were collected and dissolved in dichloromethane, then washed with aqueous NaHCO3 (150 mL), water (150 mL) and brine (100 mL). The organic phase was dried over Na2SO4, loaded on silica gel, and purified by flash chromatography (hexanes/ethyl acetate 20:1). The fraction one was collected and concentrated and white solid (16) was obtained (2.89 g, 42% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:13]3[CH:21]=[C:20]4[C:16]([CH:17]=[N:18][NH:19]4)=[CH:15][C:14]=3[CH3:22])[CH:8]=[C:9](F)[CH:10]=2)[N:5]=[N:4][C:3]=1[C:23]([NH2:25])=[O:24].CCN(C(C)C)C(C)C.[NH:35]1[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]1>CC(N(C)C)=O>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:13]3[CH:21]=[C:20]4[C:16]([CH:17]=[N:18][NH:19]4)=[CH:15][C:14]=3[CH3:22])[CH:8]=[C:9]([N:35]3[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]3)[CH:10]=2)[N:5]=[N:4][C:3]=1[C:23]([NH2:25])=[O:24]
Reactant: Cc1cc2cn[nH]c2cc1-c1cc(F)cc2c(N)c(C(N)=O)nnc12
Reactant: OC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc2cn[nH]c2cc1-c1cc(N2CCC(O)CC2)cc2c(N)c(C(N)=O)nnc12
Temperature: 140 °C
Yield: 24.4 %

Procedure:
The mixture of 4-amino-6-fluoro-8-(5-methyl-1H-indazol-6-yl)cinnoline-3-carboxamide (200 mg, 0.59 mmol), DIPEA (1000 mg), piperidin-4-ol (573 mg) and DMA (4 mL) was heated at 140° C. in a microwave under N2 for 3 h. The mixture was cooled, concentrated and purified directly with prep-HPLC to give the title compound as solid (60 mg, yield=24%). 1H NMR (400 MHz, DMSO-d6): δ 12.93 (1H, s), 8.27 (1H, s), 8.02 (1H, s), 7.60 (1H, s), 7.48-7.47 (3H, m), 7.35 (1H, s), 4.74 (1H, d, J=4.4 Hz), 3.89-3.86 (2H, m), 3.75-3.72 (m, 1H), 3.17-3.12 (2H, m), 2.00 (3H, s), 1.87-1.84 (2H, m), 1.53-1.49 (2H, m); LC-MS (5-95% ACN in H2O gradient with 0.02% NH4OAc, tR 2.809 minutes); ESI+APCI m/z [M+H]+ 418.
Reaction SMILES: [NH2:1][C:2]1[C:13]([C:14]([O:16]CC=C)=[O:15])=[C:5]2[N:6]=[CH:7][C:8]([CH2:10][C:11]#[N:12])=[CH:9][N:4]2[N:3]=1.C1([SiH3])C=CC=CC=1>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:13]([C:14]([OH:16])=[O:15])=[C:5]2[N:6]=[CH:7][C:8]([CH2:10][C:11]#[N:12])=[CH:9][N:4]2[N:3]=1
Reactant: C=CCOC(=O)c1c(N)nn2cc(CC#N)cnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Product: N#CCc1cnc2c(C(=O)O)c(N)nn2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a suspension of allyl 2-amino-6-(cyanomethyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylate 4c (10.2 g, 39.65 mmol) in DCM (350 mL) was added phenylsilane (8.581 g, 9.773 mL, 79.3 mmol), followed by Pd(PPh3)4 (1.5 g, 1.298 mmol). The reaction was stirred at room temperature for 2 h. The reaction mixture was filtered and the solid was washed with DCM and dried under vacuum to provide 2-amino-6-(cyanomethyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 5c as a yellow solid (8.61 g, 100% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][CH2:13][C:14]2[N:15]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][O:27][C:28]4[CH:29]=[CH:30][CH:31]=[C:32]5[C:37]=4[N:36]=[C:35]([CH3:38])[CH:34]=[CH:33]5)[C:20]=3[Cl:39])[CH:16]=[CH:17][CH:18]=2)=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH3:48][C:49]1[N:57]=[CH:56][CH:55]=[CH:54][C:50]=1[C:51](Cl)=[O:52]>ClCCl>[Cl:39][C:20]1[C:21]([CH2:26][O:27][C:28]2[CH:29]=[CH:30][CH:31]=[C:32]3[C:37]=2[N:36]=[C:35]([CH3:38])[CH:34]=[CH:33]3)=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[N:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[CH2:13][NH:12][C:10](=[O:11])/[CH:9]=[CH:8]/[C:5]1[CH:6]=[N:7][C:2]([NH:1][C:51](=[O:52])[C:50]2[CH:54]=[CH:55][CH:56]=[N:57][C:49]=2[CH3:48])=[CH:3][CH:4]=1
Reactant: Cc1ncccc1C(=O)Cl
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(-n4cccc4CNC(=O)/C=C/c4ccc(N)nc4)c3Cl)c2n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(-n4cccc4CNC(=O)/C=C/c4ccc(NC(=O)c5cccnc5C)nc4)c3Cl)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a mixture of 2-[(E)-3-(6-aminopyridin-3-yl)acryloylaminomethyl]-1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]pyrrole (152 mg) and triethylamine (96 mg) in dichloromethane (3 ml) was added 2-methylnicotinoyl chloride hydrochloride (115 mg) under nitrogen in ice water bath and stirred for 1 hour at the same temperature. The reaction solvent was concentrated in vacuo and the residue was dissolved in methanol. To the solution was added 1M sodium hydroxide solution (0.5 ml) and stirred for 30 minutes. The solution was evaporated and partitioned between chloroform and water. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography on silica gel (ethyl acetate) to give 1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]-2-[(E)-3-[6-[2-methylnicotinamido]pyridin-3-yl]acryloylaminomethyl]pyrrole (124 mg) as an amorphous powder. NMR (DMSO6, δ): 2.57 (3H, s), 4.26 (3H, s), 4.06-4.17 (1H, m), 4.21-4.33 (1H, m), 5.35-5.47 (2H, m), 6.18-6.25 (2H, m), 6.63 (1H, d, J=16 Hz), 6.85-6.90 (1H, m), 7.24 (1H, d, J=8 Hz), 7.29-7.36 (2H, m), 7.36-7.47 (3H, m), 7.53 (1H, d, J=8 Hz), 7.64 (1H, d, J=8 Hz), 7.73 (1H, d, J=8 Hz), 7.88 (1H, d, J=8 Hz), 8.03 (1H, d, J=8 Hz), 8.16-8.31 (3H, m), 8.51-8.57 (2H, m).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=N1.[C:28]([O:32][C:33]([NH:35][CH:36]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][CH:42]=1)[C:37]([OH:39])=O)=[O:34])([CH3:31])([CH3:30])[CH3:29].N1CCCC1.C(N1CCOCC1)C>CN(C=O)C>[C:28]([O:32][C:33]([NH:35][CH:36]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][CH:42]=1)[C:37]([N:10]1[CH2:11][CH2:16][CH2:15][CH2:14]1)=[O:39])=[O:34])([CH3:29])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(C#N)cc1)C(=O)O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CCN1CCOCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(C#N)cc1)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
7.5 g of BOP are added to a mixture of 4.06 g of 2-(tert-butoxycarbonylamino)-3-(4-cyanophenyl)propionic acid and 1.15 ml of pyrrolidine in 20 ml of DMF, and the mixture is stirred for 2 hours at RT, while maintaining the pH at 7 by adding N-ethylmorpholine. The reaction mixture is concentrated under vacuum and the residue is chromatographed on silica gel, eluting with a chloroform/MeOH mixture (95/5; v/v). 3.8 g of the expected product are obtained.
Reaction SMILES: [C:1]([O:6][OH:7])([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[K+].[OH-].[Na+].[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].Cl.CCCCCCCCCC(C)C>O>[C:12]([O:7][O:6][C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCC(C)(C)OO
Agent: CCCCCCCCCC(C)C
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCC(C)(C)OOC(=O)C(C)(C)C
Yield: 93.9 %

Procedure:
Before the start of the reaction, the loop reactor is filled with a solution of 23.1% by weight of tert-amyl hydroperoxide, 9.9% by weight of potassium hydroxide and 8.3% by weight of sodium hydroxide in water. Initially 20.0 kg/h of a solution of 88% by weight of tert-amyl hydroperoxide in water, 15.8 kg/h of a solution of 45% by weight of potassium hydroxide in water, 11.8 kg/h of a solution of 50% by weight of sodium hydroxide in water, 24.2 kg/h of water and 18.0 kg/h of pivaloyl chloride are then fed to the loop reactor. Cooling with cooling water keeps the internal temperature at 18° C. in the loop reactor and at 10° C. in the stirred cell reactor. The partial neutralization is effected with 11.4 kg/h of 31% by weight hydrochloric acid with addition of 7.4 kg/h of isododecane at a temperature of 10° C. The organic phase is extracted with 27.8 kg/h of a 16% by weight aqueous solution of potassium hydroxide. This affords 29.4 kg/h of aqueous extract comprising 5.8% by weight of tert-amyl hydroperoxide and 15.1% by weight of potassium hydroxide, which are feeded into the loop reactor. From the time at which aqueous extract is recycled into the loop reactor, the metered addition of the feedstocks is changed to 18.2 kg/h of a solution of 88% by weight of tert-amyl hydroperoxide in water, 5.8 kg/h of a solution of 45% by weight of potassium hydroxide in water and 6.6 kg/h of water. After the extraction, the organic phase is washed with 36 kg/h of a solution of 5% by weight of sodium sulphite and 0.2% by weight of sulphuric acid, and dried by stripping at 20° C. and 45 mbar. 34.4 kg/h of a 76.6% by weight solution of tert-amyl peroxypivalate in isododecane are obtained (93.9% yield based on pivaloyl chloride).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[Si:18]([O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>>[Si:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[C:2]([Cl:1])[CH:3]=2)=[CH:30][CH:31]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: O=Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(C=O)c(Cl)c2)cc1

Procedure:
The title compound was prepared by reacting trifluoro-methanesulfonic acid 3-chloro-4-formyl-phenyl ester (1.78 g, 6.18 mmol) with 4-tert-butyl-dimethylsilyoxyphenylboronic acid (2.03 g, 8.03 mmol) according to Method B to yield 0.92 g (43%) of white solid: mp 38-39° C.; 1H NMR (DMDO-d6); δ 0.23 (6H, s), 0.97 (9H, s), 6.98 (2H, d, J=8.79 Hz), 7.74 (2H, d, J=8.79 Hz), 7.81 (1H, d, J=7.81 Hz), 7.89 (1H, d, J=1.95 Hz), 7.91 (1H, d, J=7.81 Hz), 10.34 (1H, s); MS (ESI) m/z 231/233 (M−H)−(deprotected product ion).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH:13]=[O:14])[CH:9]=2)[C:4](=[O:15])[O:3]1.BrC1C=C2C(=CC=1)C(=O)O[C@@H](C)C2>>[CH3:1][C@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH:13]=[O:14])[CH:9]=2)[C:4](=[O:15])[O:3]1
Reactant: C[C@@H]1Cc2cc(CC=O)ccc2C(=O)O1
Agent: C[C@H]1Cc2cc(Br)ccc2C(=O)O1
Product: C[C@H]1Cc2cc(CC=O)ccc2C(=O)O1

Procedure:
(S)-2-(3-Methyl-1-oxoisochroman-6-yl)acetaldehyde was prepared in a similar manner as (R)-2-(3-methyl-1-oxoisochroman-6-yl)acetaldehyde except starting from (3S)-6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:9]#[CH:10])[CH:8]=1)#[N:2]>O1CCCC1.[C].[Pd]>[C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH2:9][CH3:10])[CH:8]=1)#[N:2]
Reactant: C#Cc1cncc(C#N)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1cncc(C#N)c1
Yield: 84.3 %

Procedure:
3-Cyano-5-ethynylpyridine (1 g) was dissolved in tetrahydrofuran (30 ml) and subjected to catalytic hydrogenation under hydrogen stream in the presence of 10% palladium-carbon (100 mg) as a catalyst. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure to give 0.87 g of 3-cyano-5-ethylpyridine (yield, 84%). 1H-NMR (90 MHz, CDCl3): δ (ppm) 8.58(1H, H-2), 8.39(1H, H-6), 7.77(1H, H-4), 2.72(2H, q, J=7.5Hz, Pyridine-CH2CH3), 1.26(3H, t, J=7.5Hz, Pyridine-CH2CH3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:20])[CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]([OH:19])=O)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:22][C:23]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:24]=1[OH:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:30][C:24]1[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:23]=1[NH:22][C:17]([C:15]1[O:14][N:13]=[C:12]([O:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:20])[CH:16]=1)=[O:19]
Reactant: Nc1cc(O)ccc1O
Reactant: C[C@@H](COc1cc(C(=O)O)on1)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](COc1cc(C(=O)Nc2cc(O)ccc2O)on1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.9 %

Procedure:
To a solution of 3-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)isoxazole-5-carboxylic acid (1.5 g), 2-aminobenzene-1,4-diol hydrochloride (0.847 g) and HATU (1.99 g) in DMF (20 mL) was added N,N-diisopropylethylamine (1.80 mL), and the mixture was stirred at room temperature for 5 hr. The solvent was evaporated under reduced pressure, 0.1M hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (1.11 g).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1[C:28](C2C=CC=CC=2)=CS[C:25]=1C(OC)=O.C(OCC)(OCC)OCC.C(C1CCC(N)CC1)(C)C>C(O)(=O)C>[CH:24]([CH:4]1[CH2:5][CH2:6][CH:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:2][CH2:3]1)([CH3:28])[CH3:25]
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: CC(C)C1CCC(N)CC1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: CC(C)C1CCC(n2cnc3c(-c4ccccc4)csc3c2=O)CC1
Yield: 58.4 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1 ml), 4-isopropylcyclohexylamine (0.148 ml, 0.90 mmol), and acetic acid (0.1 ml) were used to give 88.5 mg (0.25 mmol, 58.4% yield) of the title compound.
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][N:20](CC(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:31]>C(OCC)C.CO>[ClH:31].[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CN1CCN(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: c1ccc(C2CC(c3csc(N4CCNCC4)n3)=NO2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1-piperazineacetate (i.e. the product of Example 7, Step D) (0.7 g, 1.686 mmol) in diethyl ether (10 mL) was added a 2 M solution of hydrogen chloride in methanol (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 8 h. The resulting white precipitate was filtered, and dried to give 500 mg of the title compound as a white solid.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:21]([C:22]4[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH2:28])=[CH:24][CH:23]=4)[C:16]4=[N:17][CH:18]=[CH:19][CH:20]=[C:15]4[N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Si]([O:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][CH:57]2[CH2:59][O:58]2)=[CH:51][CH:50]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:21]([C:22]4[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH:28][CH2:59][C@H:57]([OH:58])[CH2:56][O:55][C:52]5[CH:53]=[CH:54][C:49]([OH:48])=[CH:50][CH:51]=5)=[CH:24][CH:23]=4)[C:16]4=[N:17][CH:18]=[CH:19][CH:20]=[C:15]4[N:14]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(-n2c(-c3ccc(C4CCCCC4)cc3)nc3cccnc32)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Oc1ccc(OC[C@@H](O)CNCCc2ccc(-n3c(-c4ccc(C5CCCCC5)cc4)nc4cccnc43)cc2)cc1
Yield: 42.6 %

Procedure:
4-[2-(4-Cyclohexylphenyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenethylamine (0.37 g, 0.93 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.377 g, 0.93 mmol) according to Procedure G (eluant: 20:1 going to 5:1 chloroform-methanol) to give the title compound (0.317 g, 0.396 mmol).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[S:12]1[CH2:16][C:15](=[O:17])[NH:14][C:13]1=[O:18]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[C:16]3[S:12][C:13](=[O:18])[NH:14][C:15]3=[O:17])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: O=C1CSC(=O)N1
Product: O=C1NC(=O)C(=Cc2ccc3c(c2)CCO3)S1

Procedure:
Following the general method as outlined in Example 1, starting from 2,3-dihydro-1-benzofuran-5-carbaldehyde and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Br[CH2:13][CH2:14][Cl:15].O>CCCCC.CN(C=O)C>[Cl:15][CH2:14][CH2:13][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: ClCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: O
Solvent: CN(C)C=O
Product: ClCCn1ccc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
NaH (0.253 g; 0.11 mole of 60% NaH in suspension in mineral oil, previously washed with pentane) is added to a solution of indole (1.17 g; 0.1 mole) in 10 mL of DMF placed under a nitrogen atmosphere, then the reaction mixture is stirred for 30 minutes at ambient temperature. 1-bromo 2-chloroethane is then added. After reaction for 2 hours, the reaction mixture is treated by the slow addition of water and extracted with ethyl acetate. The organic phase is washed with water then with a saturated aqueous solution of NaCl, dried over anhydrous Na2SO4, filtered and evaporated under vacuum. The residue obtained is purified by chromatography on silica gel. The 1-(2-chloroethyl)indole is obtained pure with a yield of 80%.
Reaction SMILES: C[O:2][C:3]1[CH:30]=[CH:29][C:6]([NH:7][C:8]([CH2:10][NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:22])[CH2:14][CH2:13]2)=[O:9])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([NH:7][C:8]([CH2:10][NH:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH2:20][C:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:22])[CH2:16][CH2:17]2)=[O:9])=[CH:29][CH:30]=1
Reactant: COc1ccc(NC(=O)CNC2CCN(CCCC(=O)c3ccccc3)CC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(CNC1CCN(CCCC(=O)c2ccccc2)CC1)Nc1ccc(O)cc1

Procedure:
4-p-Methoxyanilinocarbonylmethylamino-1-(4 -phenyl-4-oxobutyl)-piperidine may be reacted with pyridine hydrochloride to give the title compound.