Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:50][CH:51]1[C@H:55]2[C@H:56](OC3CCCCO3)[N:57](C(OC(C)(C)C)=O)[C:58]3[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[CH:62][C:59]=3[C:60](=[O:61])[N:54]2[CH2:53][C:52]1=[CH2:82])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[C@H:22]2[C@H:23](OC3CCCCO3)[N:24](C(OC(C)(C)C)=O)[C:25]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:26]=3[C:27](=[O:28])[N:21]2[CH2:20][C:19]1=[CH2:49].C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:16]([O:17][CH:18]1[C@@H:22]2[CH:23]=[N:24][C:25]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:26]=3[C:27](=[O:28])[N:21]2[CH2:20][C:19]1=[CH2:49])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:50][CH:51]1[C@@H:55]2[CH:56]=[N:57][C:58]3[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[CH:62][C:59]=3[C:60](=[O:61])[N:54]2[CH2:53][C:52]1=[CH2:82]
Reactant: C=C1CN2C(=O)c3cc(OC)ccc3N(C(=O)OC(C)(C)C)[C@@H](OC3CCCCO3)[C@@H]2C1OCCCCCCCCCOC1C(=C)CN2C(=O)c3cc(OC)ccc3N(C(=O)OC(C)(C)C)[C@@H](OC3CCCCO3)[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: C=C1CN2C(=O)c3cc(OC)ccc3N=C[C@H]2C1OCCCCCCCCCOC1C(=C)CN2C(=O)c3cc(OC)ccc3N=C[C@@H]12
Reaction time: 1 h
Yield: 54.1 %

Procedure:
95% TFA (2 mL) was added dropwise to dimer compound 28b (89 mg, 0.085 mmol) at 0° C. which was stirred for 1 h and then poured into saturated aqueous NaHCO3 (30 mL). The mixture was extracted with chloroform (3×20 mL) and the organic layer washed with water (20 mL), brine (20 mL), dried (MgSO4) and filtered. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 29b (30 mg, 0.046 mmol, 55%) as a solid: [α]27D=+308° (c=0.24, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.30-1.39 (m, 6H, 15-H, 16-H), 1.40-1.50 (m, 4H, 14-H), 1.82-1.91 (m, 4H, 13-H), 2.89-2.97 (m, 2H, 1-H), 3.06-3.16 (m, 2H, 1-H), 3.81-3.90 (m, 2H, 11a-H), 3.93 (s, 6H, 7-OMe), 3.98-4.10 (m, 4H, 12-H), 4.28 (s, 4H, 3-H), 5.16-5.19 (m, 4H, 2a-H), 6.79 (s, 2H, 9-H), 7.48 (s, 2H, 6-H), 7.66 (d, 2H, J=4.44 Hz, 11-H); 13C NMR (CDCl3, 100 MHz): δ 25.8, 28.8, 29.2, 29.4, 35.2, 51.3, 53.8, 56.2, 69.0, 109.3, 110.3, 111.3, 119.5, 140.6, 141.7, 151.0, 162.4, 164.8; IR (neat): 2928, 2854, 1624, 1599, 1506, 1464, 1429, 1381, 1261, 1216, 1096, 729 cm−1; MS (ES+) m/z (relative intensity) 641 ([M+H]+., 100), 642 ([M+2H]+., 52), 339 (97).
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[CH:14](=O)/[CH:15]=[CH:16]/[CH3:17].[C:19]([O-:22])(=[O:21])[CH3:20].[Na+].CC(OC(C)=O)=O>>[CH2:12]([O:11][C:1]([C:2]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:17][CH2:16][CH:15]=[CH:14][CH:3]1[O:22][C:19](=[O:21])[CH3:20])=[O:10])[CH3:13]
Reactant: C=C(C(=O)OCC)c1ccccc1
Reactant: C/C=C/C=O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C1(c2ccccc2)CCC=CC1OC(C)=O
Reaction time: 6 h

Procedure:
1 mole (170 g) of ethyl atropate, 210 g of crotonaldehyde, 150 g of anhydrous sodium acetate and 0.6 of acetanhydride are heated to boiling for 6 h. while stirring. Subsequently the main amount of the liquid phase is distilled off under vacuum, and the residue is extracted with 1 liter of hot ligroin. The residue of the ligroin phase is distilled. The product -- although being pure according to gas chromatography -- distills in a wide boiling range: b.p. °, 1 130°-165° C. Yield: 105 g. It crystallizes when allowed to stand. M.P. 72°-73° C (from petroleum ether).
Reaction SMILES: C(NCC)C.[C:6]1([C:12]([CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)O)=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:22](#[N:26])[CH2:23][C:24]#[N:25].O>CN(C=O)C>[NH2:26][C:22]1[O:13][C:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:23]=1[C:24]#[N:25]
Reactant: N#CCC#N
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Solvent: O
Solvent: CCNCC
Solvent: CN(C)C=O
Product: N#Cc1c(N)oc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
Diethylamine (13.8 g) was added dropwise over a period of 30 min to a mixture of benzoin (10 g) and malononitrile (3.8 g) in DMF (30 ml) at 0° C. (the internal temperature should not exceed 40° C.). After the resulting mixture was stirred at room temperature for 16 h, water (100 mL) was added. The resulting precipitate was filtered, washed with sufficient amount of water, then with hexanes, and dried. The solid was recrystallized from ethanol to provide yellowish-brown solid product of the title compound (6 g, 49%). 1H NMR (300 MHz, CDCl3): δ 7.47-7.34 (m, 8H), 7.28-7.18 (m, 2H), 4.94 (br, 2H). LC-MS (ESI) m/z 261.1 (M+H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:21]=[CH:20][C:6]2[N:7]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])=[N:9][C:5]=2[CH:4]=1.C(N(CC)C(C)C)(C)C.[C:31]([O:35][C:36]([NH:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[CH2:44][CH:43]([C:48](O)=[O:49])[CH2:42]2)=[O:37])([CH3:34])([CH3:33])[CH3:32].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[C:31]([O:35][C:36](=[O:37])[NH:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[CH2:44][CH:43]([C:48]([N:17]1[CH2:16][CH2:15][CH:14]([N:7]3[C:6]4[CH:20]=[CH:21][C:3]([CH3:2])=[CH:4][C:5]=4[N:9]=[C:8]3[C:10]([OH:13])([CH3:12])[CH3:11])[CH2:19][CH2:18]1)=[O:49])[CH2:42]2)([CH3:34])([CH3:32])[CH3:33]
Reactant: Cc1ccc2c(c1)nc(C(C)(C)O)n2C1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)CC(C(=O)O)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)nc(C(C)(C)O)n2C1CCN(C(=O)C2Cc3ccc(NC(=O)OC(C)(C)C)cc3C2)CC1
Reaction time: 0.17 h
Yield: 90.8 %

Procedure:
To a solution of 2-(5-methyl-1-piperidin-4-yl-1H-benzoimidazol-2-yl)-propan-2-ol hydrochloride salt (158 mg, 0.55 mmol) in DMF (5 ml) was added N,N-diisopropylethylamine (150 mg, 1.15 mmol). After stirring for 10 minutes, 5-tert-butoxycarbonylamino-indan-2-carboxylic acid (140 mg, 0.55 mmol) was added to the reaction mixture followed by EDCI (195 mg, 1.10 mmol) and HOBT (137 mg, 1.10 mmol). After stirring at rt for 4 hours, the reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated NaHCO3, brine, and dried over Na2SO4. The extracts were filtered and concentrated in vacuo to afford (2-{4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-benzoimidazol-1-yl]-piperidine-1-carbonyl}-indan-5-yl)-carbamic acid tert-butyl ester (266 mg, 98%) as a white solid without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O>C1(C)C=C(C)C=C(C)C=1>[C:7]1(=[O:9])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[CH:2]#[CH:3]
Reactant: COC(=O)CCCCCN
Solvent: Cc1cc(C)cc(C)c1
Product: C#C
Product: O=C1CCCCCN1
Temperature: 140 °C
Yield: 260.4 %

Procedure:
A solution of 37.1 g (0.256 mol) of methyl 6-aminocaproate in 723 g of mesitylene is stirred under reflux at 140° C./500 bar for 12 h. Evaporating off the mesitylene under reduced pressure leaves 46.4 g of a caprolactam-acetylene mixture which, according to HPLC, contains 58.2% of caprolactam, which corresponds to 27.0 g (0.239 mol) and a yield of 93.4%.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH:13]([OH:16])(C)[CH3:14].[NH2:17]C(O)C.[OH-].[Na+]>O>[OH:16][CH2:13][CH2:14][NH:17][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1
Reactant: CC(C)O
Reactant: CC(N)O
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(NCCO)n1
Yield: 95.5 %

Procedure:
To a mixture of 188.6 g (1 mole) of 2-chloro-6-methoxy-3-nitropyridine with 350 ml of isopropanol, 83.5 g (1.4 mole) of aminoethanol are added drop by drop with cooling while stirring and maintaining a temperature of 25°-30° C. After the addition, the reaction mixture is continued to be stirred for another hour at a maximum of 30° and then 47.5 ml of 50% caustic soda solution are added drop by drop over the course of about 2 hours at a maximum temperature of 30° C. After 6 hours of stirring, 500 ml of water are stirred in and the product is filtered off with suction, is then washed sufficiently with water and is then dried. The compound is obtained in the form of a yellow powder with a melting point of 121°-2° C. and in a yield of 95.5% of theory.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[F:15])[CH:10]=O>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH2:2])[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: C=Cc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of Ph3PCH3Br (57 g) in THF (240 mL) at 0° C. was dropwise added n-BuLi (1.6 N, 100 mL). The resulting mixture was allowed to warm to room temperature and stirred for 1 h. After recooling to 0° C., a solution of 3-bromo-4-fluoro-benzaldehyde (20.3 g) in THF (20 mL) was added. The resulting mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched with water, concentrated, and extracted with methylene chloride. The combined organic layers were dried over magnesium sulfate, concentrated under vacuum. The crude product was purified by flash chromatography eluting with 10% ethyl acetate in hexanes to give the title compound as an oil (18 g).
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([CH2:10][CH:11]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])[CH2:9][CH2:8][CH2:7][CH2:6]1.[OH-].[NH4+]>C(Cl)Cl>[CH:5]1([CH2:10][CH:11]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COc1cccc(C(CC2CCCC2)C(=O)Nc2nccs2)c1
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
A 1.0M solution of boron tribromide in methylene chloride (3.53 mL, 3.53 mmol) at 25° C. was treated with a solution of 3-cyclopentyl-2-(3-methoxy-phenyl)-N-thiazol-2-yl-propionamide (prepared as in Example 110, 0.11 g, 0.35 mmol) in methylene chloride (3.5 mL). This solution was stirred at 25° C. for 1 h. At this time, the reaction was cooled to 0° C. and treated with a dilute aqueous ammonium hydroxide solution. This mixture was stirred at 0° C. for 15 min. At this time, the aqueous layer was separated from the organic layer. The aqueous layer was extracted with chloroform (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-hydroxy-phenyl)-N-thiazol-2-yl-propionamide (50 mg, 44.7%) as a white solid: mp 177–179° C.; EI-HRMS m/e calcd for C17H20N2O2S (M+) 316.1245 found 316.1244.
Reaction SMILES: N1CCCC1.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=[O:18])=[CH:10][CH:9]=1.[N+:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)([O-:21])=[O:20]>CO>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14](=[CH:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=3)[C:15]2=[O:18])=[CH:10][CH:9]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Solvent: CO
Solvent: C1CCNC1
Product: COc1ccc2c(c1)C(=O)C(=Cc1cccc([N+](=O)[O-])c1)CC2
Temperature: 25 °C
Yield: 71 %

Procedure:
2.5 mL (30.1 mmol) of pyrrolidine were added to a room temperature (about 25° C.) solution of 5.30 g (30.1 mmol) of 7-methoxy-1-tetraione and 4.55 g (30.1 mmol) of 3-nitrobenzaldehyde in 25 mL methanol. The reaction flask was fitted with a soxhlet extractor containing a thimble filled with 3 Å molecular sieves and a reflux condenser was placed on top of the soxhlet extractor. The reaction mixture was heated to reflux under N2 for 18 hours, cooled to room temperature and filtered. The precipitate was washed twice with CH3OH, and then dried on the funnel for 24 hours to yield 6.62 g of light tan powder. (71% yield).
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[C:3](=[O:6])[CH2:4][CH3:5].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Br)=[CH:22][CH:21]=1.[OH-].[Na+]>CS(C)=O.O>[OH:1][C:2]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:11][CH:12]=1)([C:3](=[O:6])[CH2:4][CH3:5])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1
Reactant: CCC(=O)C(O)c1ccc(N2CCOCC2)cc1
Reactant: Cc1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCC(=O)C(O)(Cc1ccc(C)cc1)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-Hydroxy-1-(4-morpholinophenyl)-butan-2-one, one equivalent of 4-methylphenylmethyl bromide and 1.2 equivalent of sodium hydroxide are suspended in dimethyl sulfoxide and the resulting mixture is stirred at room temperature for 24 hours. The reaction mixture is diluted with the same amount of water and extracted several times with dichloromethane. The combined organic extracts are dried over sodium sulfate and evaporated to give crude 2-hydroxy-2-(4-morpholinophenyl)-1-(4-methylphenyl)-pentan-3-one as a viscous oil. The compound is purified by chromatography on silica gel (eluant: hexane/ethyl acetate 9:1). Pure 2-hydroxy-2-(4-morpholinophenyl)-1-(4-methylphenyl)-pentan-3-one is thus obtained as colorless crystals with a melting point of 160° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH:6]([CH3:11])[CH2:5]1)(=[O:3])[CH3:2].Cl.C[C@H]1[C@@H]([NH2:20])CCOC1>>[NH2:20][C@H:7]1[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][C@H:6]1[CH3:11]
Reactant: C[C@@H]1COCC[C@@H]1N
Reactant: CC(=O)N1CCC(=O)C(C)C1
Agent: Cl
Product: CC(=O)N1CC[C@H](N)[C@H](C)C1

Procedure:
Racemic cis 1-(4-amino-3-methyl-piperidin-1-yl)-ethanone was prepared in the same manner from racemic 1-acetyl-3-methyl-piperidin-4-one. In this instance, 1 atm H2 was used instead of 55 psi, and the HCl treatment was omitted.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:21](=[O:22])[C:20]4[CH:23]=[CH:24][S:25][C:19]=4[NH:18][C:17]3=[O:26])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[C:29]([N:18]1[C:19]2[S:25][CH:24]=[CH:23][C:20]=2[C:21](=[O:22])[N:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=3)[CH2:9][CH2:10]2)[C:17]1=[O:26])(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3sccc3c2=O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)n1c(=O)n(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c(=O)c2ccsc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.8 %

Procedure:
A mixture of 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]thieno[2,3-d]pyrimidine-2,4-dione of Example 2 (1.7 g, 4.2 mmol), acetyl chloride (0.33 ml, 4.6 mmol) and triethylamine (1.8 ml, 12.6 mmol) in methylene chloride (40 ml) was stirred at room temperature for two days. The resultant solution was washed with H2O (2×50 ml), and then dried over magnesium sulfate. The solvent was evaporated in vacuo, and the resultant residue was purified by flash chromatography on silica gel 60 (80 g) using 2% methanol in methylene chloride as the eluant to give the named compound (1.3 g, 69% yield) as a colorless solid, mp 137°-141° C. IR(KBr): 1630, 1700 and 1775 cm-1 ; MS (DCI), m/z 444 (MH+); 1H NMR (CDCl3): δ 1.76-1.85 (m, 4H), 2.19-2.25 (m, 2H), 2.70 (t, J=7 Hz, 2H), 2.86 (s, 3H), 3.12-3.25 (m, 3H), 4.22 (t, J=7 Hz, 2H), 7.07 (d, J=6 Hz, 1H), 7.13 (t, J=8 Hz, 2H), 7.40 (d, J=6 Hz, 1H), 7.94-7.97 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](C)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:12]N1C(=O)CCC1=O>ClCCl>[Cl:1][C:2]1[C:3]2[C:10]([Cl:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: ClCCl
Product: Clc1c[nH]c2ncnc(Cl)c12
Temperature: 43 °C
Yield: 81.8 %

Procedure:
Following the procedure in Pdulo, J. S.; Saxena, N. K.; Nassiri, M. R.; Turk, S. R.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 31:2086 (1988), 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (Example 1A, 20. g, 0.13 mol) was suspended in anhydrous dichloromethane (500 mL), followed by addition of N-chlorosuccinimide (20.8 g, 0.160 mol). The reaction mixture was refluxed at 43° C. for 8 hours. The reaction was cooled down, and the white solid was filtered, washed with dichloromethane (300 mL), and dried to give 4,5-dichloro-7H-pyrrolo[2,3-d]pyrimidine (20 g, 83%)
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:39])[C:8]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]5[C@H:27]([C:28](C)(C)[O:29][SiH2]C(C)(C)C)[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.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:39])[C:8]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([OH:24])[C@H:27]([OH:26])[CH2:28][OH:29])[CH:18]=[CH:17][C:9]=4[C:10]([CH3:15])([CH3:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: CC1(C)O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)[C@@H](COc2ccc3c(c2)C(=O)c2c([nH]c4cc(Br)ccc24)C3(C)C)O1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)c2ccc(OC[C@@H](O)[C@H](O)CO)cc2C(=O)c2c1[nH]c1cc(Br)ccc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
3-Bromo-9-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy]-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ7-1, 13.7 mg, 0.0223 mmol) was dissolved in THF (0.15 mL) and methanol (0.1 mL), added with 0.5 M sulfuric acid (0.05 mL), and then stirred at 60° C. for 3 hr. After cooling, the reaction solution was added with saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After filtration and the concentration under reduced pressure, the resulting solid was washed with dichloromethane to obtain the title compound (white solid, 8.4 mg, 82%).
Reaction SMILES: [BH4-].[Na+].[N+:3]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:5])=[O:4].C(O)(=O)C>O1CCOCC1.C(O)C.O1CCOCC1>[N+:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])C=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In a 500 mL two-necked flask equipped with a thermometer and a pressure-equalizing dropping funnel, NaBH4 (5.33 g, 0.140 mol) was suspended in 1,4-dioxane/ethanol (100 mL/30 ml). β-Nitrostyrene (3, 10.0 g, 67.0 mmol) in 1,4-dioxane (100 mL) was added dropwise to the solution over 45 minutes, keeping the temperature below 30° C. A fine slurry formed during the addition. After the addition the reaction mixture was stirred overnight, then ice/water (125 mL) was added, and a 50% solution of acetic acid was added to neutralize excess NaBH4; the clear solution was then concentrated in vacuo and the residue was dissolved in water and extracted twice with CH2Cl12. The organic phase was washed with water (2×30 mL) and brine (1×30 mL), dried (Na2SO4), filtered and evaporated in vacuo obtaining 4 (8.4.0 g, 83%) as yellow oil. ESI-MS: 152 (MH+) (Calc. for C8H9NO2: 151).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].Cl[C:27]1[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([C:37]([O-:39])=[O:38])=[CH:29][N:28]=1.N12CCN(CC1)C[CH2:41]2>C(N(CC)CC)C>[CH3:41][O:39][C:37]([C:30]1[C:31]([C:33]([F:36])([F:35])[F:34])=[N:32][C:27]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:25])[C:10]([C:16]3[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)([OH:15])[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=2)=[N:28][CH:29]=1)=[O:38]
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Reactant: O=C([O-])c1cnc(Cl)nc1C(F)(F)F
Reactant: C1CN2CCN1CC2
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3cc(C)c(=O)n(C)c3)C(F)(F)F)c(Cl)c2)nc1C(F)(F)F

Procedure:
In analogy to Example 163, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5) was reacted with 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate in the presence of triethylamine and 1,4-diazabicyclo[2.2.2]octane to give the title compound as a colorless solid. MS (m/e)=580.2 [M+H+].
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][S:15]([NH2:18])(=[O:17])=[O:16])=[N:5][N:4]=1.[CH3:19][O:20][C:21]1[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][C:29](=O)[O:30]C2C=CC=CC=2)[N:22]=1.C1CCN2C(=NCCC2)CC1.Cl>O1CCOCC1.O>[CH3:19][O:20][C:21]1[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][C:29]([NH:18][S:15]([CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:6]2[O:7][C:3]([S:2][CH3:1])=[N:4][N:5]=2)(=[O:17])=[O:16])=[O:30])[N:22]=1
Reactant: COc1nc(C)nc(NC(=O)Oc2ccccc2)n1
Reactant: CSc1nnc(-c2ccccc2CS(N)(=O)=O)o1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)Cc2ccccc2-c2nnc(SC)o2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.5 %

Procedure:
By the procedure of Example 4, 0.62 g of the sulfonamide of Example 3 was reacted with 0.57 g of phenyl (4-methoxy-6-methyl-1,3,5-triazin-2-yl)carbamate and 0.33 g of DBU in 10 ml of p-dioxane. After stirring two hours at room temperature the solution was diluted with about 75 ml of water and acidified with concentrated hydrochloric acid (red to litmus). Following filtration, the residue was washed with 1×5 ml of warm ethyl acetate to give 0.28 g of the subject compound; m.p. 175°-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([OH:22])=O)=[CH:12][N:11]=1.[CH:23]1([NH2:27])[CH2:26][CH2:25][CH2:24]1>>[CH:23]1([NH:27][C:20]([C:13]2[C:14]([C:16]([F:19])([F:18])[F:17])=[N:15][C:10]([NH:9][C:3]3[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=3[Cl:1])=[N:11][CH:12]=2)=[O:22])[CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1cnc(Nc2cc(Cl)ccc2Cl)nc1C(F)(F)F
Reactant: NC1CCC1
Product: O=C(NC1CCC1)c1cnc(Nc2cc(Cl)ccc2Cl)nc1C(F)(F)F

Procedure:
In a manner similar to Reference Example 1(c) 2-(2,5-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (50 mg) and cyclobutylamine (19 μl)-afforded the title compound (56 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]([CH3:27])[CH3:26])[CH2:20][CH2:19]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]3[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([CH2:24][N:25]([CH3:27])[CH3:26])[CH2:22][CH2:23]2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CCCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure A-1, 1-{6-bromo-4-[trans-4-((dimethylamino)methyl)cyclohexylamino]quinolin-3-yl}butan-1-one (48 mg, 0.110 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (45 mg, 0.165 mmol) to afford the desired product (36 mg, 67%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.14 (s, 1H), 8.47 (s, 1H), 8.26 (dd, J=8.7, 1.8 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.58 (s, 1H), 7.50 (d, J=11.3 Hz, 1H), 4.52 (s, 1H), 3.16-3.05 (m, 4H), 2.95 (s, 6H), 2.49-2.43 (m, 2H), 2.08-2.01 (m, 2H), 1.85-1.74 (m, 4H), 1.41-1.32 (m, 1H), 1.09-1.02 (t, J=7.4 Hz, 3H); ESI MS m/z 498 [C28H33ClFN3O2+H]+; HPLC>99% (AUC), tR=11.08 min.