Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.[C-:34]#[C-:35].[Si]([Li])(C)(C)C>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)([OH:13])[C:34]#[CH:35])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=1
Reactant: COc1nc2ccc(C(=O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: [C-]#[C-]
Agent: [Li][Si](C)(C)C
Solvent: C1CCOC1
Product: C#CC(O)(c1ccc2nc(OC)c(Cc3ccc(C(F)(F)F)cc3)c(Cl)c2c1)c1cnc(C)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanone (405 mg, 0.85 mmol, Intermediate 8: step b) was added THF (20 mL). The solution was cooled in a dry-ice bath and TMS-lithiumacetylide (0.5 M in Et20, 1.8 mL, 0.9 mmol) was introduced. After 60 minutes, additional TMS-lithiumacetylide (5.0 mL, 2.5 mmol, 0.5 M in Et2O) was added and the reaction mixture was stirred at room temperature overnight. After 24 hours, the reaction was quenched with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (4×40 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. Chromatography on silica gel (2% MeOH-DCM increasing to 5% 2 M NH3-MeOH) afforded the title compound and the silylated title compound. 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=1.9 Hz, 1H), 7.84-7.68 (m, 2H), 7.44 (dd, J=43.2, 8.2 Hz, 5H), 6.67 (s, 1H), 4.34 (s, 2H), 4.07 (s, 3H), 3.37 (s, 3H), 2.77 (s, 1H), 2.32-2.12 (m, 3H); MS (ESI): mass calcd. for C26H21ClF3N3O2, 499.1, m/z found 500.1 [M+H]+. 1-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-(1,2-dimethyl-1H-imidazol-5-yl)prop-2-yn-1-ol was purified by chiral chromatography (Chiralpak AD (20 μM) diacel (41 mm×41 mm), heptane:2-propanol with 2% isopropylamine (93:7)) to give 2 enantiomers. The first eluting enantiomer was Example 14b and the second eluting enantiomer was Example 14c.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:13])[C:10](Cl)=[O:11].[CH3:14][C:15]1[N:19]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)[N:18]=[CH:17][C:16]=1[C:30]([NH:32][C:33]1[CH:34]=[N:35][C:36]([C:40]2[CH2:41][CH2:42][NH:43][CH2:44][CH:45]=2)=[C:37]([CH3:39])[CH:38]=1)=[O:31].ClCCl>C(O)C.O>[CH3:8][N:9]([CH3:13])[C:10]([N:43]1[CH2:44][CH:45]=[C:40]([C:36]2[N:35]=[CH:34][C:33]([NH:32][C:30]([C:16]3[CH:17]=[N:18][N:19]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=4)[C:15]=3[CH3:14])=[O:31])=[CH:38][C:37]=2[CH3:39])[CH2:41][CH2:42]1)=[O:11]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCNCC1
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCN(C(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (33 μl) and dimethylcarbamoyl chloride (22 μl) were added to a mixture of 5-methyl-N-[5-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (100 mg) and dichloromethane (4.6 ml) and stirred at room temperature for two hours. Triethylamine (95 μl), water and ethanol were added to the reaction solution and the solvent was evaporated in vacuo. The precipitated solid was washed with water and ethanol to give the titled compound (66 mg) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([F:12])[CH:4]=1)#[N:2].C(Cl)(=O)C(Cl)=O.Cl.[CH2:20]([O:22][C:23](=[O:27])[CH2:24][CH2:25][NH2:26])[CH3:21].C(N(C(C)C)C(C)C)C>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:26][CH2:25][CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:27])=[O:9])=[C:5]([F:12])[CH:4]=1)#[N:2]
Reactant: CCOC(=O)CCN
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)c1ccc(C#N)cc1F
Yield: 85.9 %

Procedure:
4-Cyano-2-fluorobenzoic acid (ABCR, 1.65 g, 10 mmol) was dissolved in DCM (40 mL). DMF (8 μl) was added at RT followed by oxalyl chloride (0.98 mL, 11.6 mmol). Once the gas evolution has ceased, the reaction mixture was evaporated to dryness. The residue was then dissolved in DCM (10 mL) and beta-alanine ethyl ester hydrochloride (1.54 g, 10 mmol) was added followed by dropwise addition of N-ethyldiisopropylamine (3.40 mL, 20 mmol) over 10 minutes. The reaction mixture was then washed with water and a saturated aqueous solution of NaHCO3, dried with MgSO4 and evaporated in vaccuo affording the title compound (2.27 g, 86%) as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.67 (t, J=5.0 Hz, 1H), 7.97 (dd, J=10.0, 1.3 Hz, 1H), 7.79 (dd, J=7.9, 1.4 Hz, 1H), 7.71 (m, 1H), 4.08 (q, J=7.2 Hz, 2H), 3.49 (m, 2H), 2.57 (t, J=6.9 Hz, 2H), 1.19 (t, J=7.2 Hz, 3H). LC/MS (Method B): 263.2 (M−H)−. HPLC (Method A) Rt 2.68 min (Purity: 98.5%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:22][C:23]([C:25]2([NH:40]C(=O)OC(C)(C)C)[CH2:30][CH2:29][N:28]([C:31]3[C:32]4[CH:39]=[CH:38][NH:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:27][CH2:26]2)=[O:24])[CH2:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1>ClCCl>[NH2:40][C:25]1([C:23]([NH:22][CH:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)[CH2:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[O:24])[CH2:26][CH2:27][N:28]([C:31]2[C:32]3[CH:39]=[CH:38][NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(Cc2nccs2)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(C(=O)NC(Cc2nccs2)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Yield: 56.6 %

Procedure:
TFA (2.0 mL) was added to a suspension of tert-butyl 4-(1-(4-chlorophenyl)-2-(thiazol-2-yl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 96) (918 mg, 0.95 mmol) in dichloromethane (20 mL) under argon. The resulting solution was stirred at room temperature for one night. The solvents were removed in vacuo and the reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-2-(thiazol-2-yl)ethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (259 mg, 56.8%) as a white powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=2)[CH2:4][CH2:3]1>CCOC(C)=O.CO>[CH2:20]([O:19][C:12]1[CH:11]=[C:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:15]=[CH:14][C:13]=1[NH2:16])[CH3:21]
Reactant: CCOc1cc(CCN2CCN(C)CC2)ccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOc1cc(CCN2CCN(C)CC2)ccc1N
Reaction time: 8 h
Yield: 101.8 %

Procedure:
1-methyl-4-{2-[3-(ethyloxy)-4-nitrophenyl]ethyl}piperazine (0.373 g, 1.14 mmol) was placed in a 100 mL high pressure vessel and dissolved in 30 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/carbon (0.223 g, 0.057 mmol) was added followed quickly by a screw cap septum. The flask was evacuated and filled with N2 six times to remove any oxygen. The vessel was then pressurized with H2 (balloon). The solution stirred overnight. The next morning the vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to afford the title compound of step D (0.308 g, 1.16 mmol, 100%). 1H NMR (400 MHz, CDCl3) δ ppm 6.57-6.65 (m, 3H), 3.99-4.08 (m, 2H), 3.62-3.74 (m, 2H), 2.65-2.75 (m, 2H), 2.47-2.59 (m, 8H), 2.31 (s, 3H), 1.36-1.45 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[N:6]=[C:5]2[NH:21][CH2:22][C:23]([F:26])([F:25])[F:24].C(=O)([O-])[O-].[K+].[K+].[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][NH:12][C:7]2[N:6]=[C:5]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:37]4[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=4)[CH:3]=3)[N:8]=2)=[CH:15][CH:16]=1
Reactant: Fc1ccc(CNc2nc(NCC(F)(F)F)c3cc(Br)ccc3n2)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(CNc2nc(NCC(F)(F)F)c3cc(-c4ccc(F)cc4)ccc3n2)cc1
Temperature: 170 °C

Procedure:
A mixture of 6-Bromo-N2-(4-fluoro-benzyl)-N4-(2,2,2-trifluoro-ethyl)-quinazoline-2,4-diamine (34 mg, 0.08 mmol), potassium carbonate (0.4M. 0.4 ml)), tetrakis(triphenylphosphine) palladium (10 mg) and 4-fluorophenyl boronic acid in DMF (1 ml) was heated to 170° C. for 5 minutes by microwave. The residue was purified by RP HPLC, eluting with 0.1% TFA-acetonitrile, to provide the desired product (20 mg). The product was characterized as follows: MS (m/z): 445 ([M+H]+, 100); HPLC Rt=3.10 minutes (Method A).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[N:9]2[CH:10]=[C:11]([CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=3)[N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.O1CCCC1.O>CO>[Cl:3][C:4]1[N:9]2[CH:10]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:19][OH:20])=[CH:21][CH:22]=3)[N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OCc2cn3c(Cl)cccc3n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(OCc2cn3c(Cl)cccc3n2)cc1
Reaction time: 1 h
Yield: 66 %

Procedure:
Sodium borohydride (232 mg) was added to a solution of 4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzaldehyde (3.52 g) in methanol (10 ml)-tetrahydrofuran (50 ml) at 0° C. After stirring for 1 hour, water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate to obtain 4(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzylalcohol (2.34 g, yield 66%) as colorless crystals. m.p. 169-171° C.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)[N:13]=[N:12][C:11]=1[C:26]([NH:28][CH:29]1[CH2:31][CH2:30]1)=[O:27])C1C=CC=CC=1.CO>CN(C=O)C.[C].[Pd]>[CH:29]1([NH:28][C:26]([C:11]2[N:12]=[N:13][N:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=3)[C:10]=2[CH2:9][OH:8])=[O:27])[CH2:30][CH2:31]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COCc2ccccc2)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CO)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 76 %

Procedure:
To a solution of 5-[(benzyloxy)methyl]-N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (4.29 g) obtained in Example 94 in DMF (60 ml)-methanol (180 ml) was added palladium-carbon (1.0 g). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 5 days, and the insoluble material was filtered off. The solvent was evaporated, and the residue was purified by silica gel column (hexane/ethyl acetate=1/1 to ethyl acetate/methanol=4/1). The resultant product was recrystallized from ethyl acetate/hexane to give the title compound as a colorless powder (2.56 g, 76%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:18][CH2:17]3)[C:5]=2[CH:6]=1.[C:28]1([CH3:55])[CH:33]=[CH:32][C:31]([C:34]([C@@:36]([C:52]([OH:54])=[O:53])([OH:51])[C@@:37]([C:42]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)=[O:43])([OH:41])[C:38]([OH:40])=[O:39])=[O:35])=[CH:30][CH:29]=1>CC(C)=O>[CH:1]1[CH:2]=[CH:3][C:4]2[S:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:18][CH2:17]3)[C:5]=2[CH:6]=1.[C:28]1([CH3:55])[CH:33]=[CH:32][C:31]([C:34]([C@@:36]([C:52]([O-:54])=[O:53])([OH:51])[C@@:37]([C:42]([C:44]2[CH:45]=[CH:46][C:47]([CH3:50])=[CH:48][CH:49]=2)=[O:43])([OH:41])[C:38]([O-:40])=[O:39])=[O:35])=[CH:30][CH:29]=1
Reactant: Cc1ccc(C(=O)[C@](O)(C(=O)O)[C@@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Agent: OCCOCCN1CCN(C2=Nc3ccccc3Sc3ccccc32)CC1
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)[C@](O)(C(=O)[O-])[C@@](O)(C(=O)[O-])C(=O)c2ccc(C)cc2)cc1

Procedure:
Quetiapine free base (3.0 g) was dissolved in acetone (30 ml) at room temperature. To this solution was added di-p-toluoyl-L-tartaric acid (1.52 g) at 30 to 35° C. The resulting mass heated to reflux and maintained for 30 minutes. This was followed by the distillation of acetone and obtained solid was further dried under vacuum to give the title compound as off white powder (3.62 g).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13](OCC)(=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CCCCCCC.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:13]([O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([OH:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)(=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CCCCCCCCC(=O)OCC
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCCCCCC
Product: CCOC(=O)CCCCCCCCC(=O)OC1CC(C)(C)N(O)C(C)(C)C1

Procedure:
When following the procedure of Example 1, equimolar amounts of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-ol and diethyl sebacate are reacted in heptane in the presence of tetraisopropyl orthotitanate, the title compound is prepared.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28](O)=[O:29])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:31]([O:38][CH2:39][CH2:40][NH:41][CH2:42][C:43]([CH3:46])([CH3:45])[CH3:44])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH2:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C:28]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:29])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33]
Reactant: O=C(O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)(C)CNCCO[Si](C)(C)C(C)(C)C
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: CC(C)(C)CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.1 %

Procedure:
To a stirred solution mixture of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (283) (230 mg, 0.57 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(2,2-dimethyl-propyl)-amine (8h) (167 mg, 0.68 mmol) in dimethylformamide (2.2 mL) were added N,N-diisopropylethylamine (0.3 mL, 1.70 mmol) and HATU (324 mg, 0.85 mmol). The reaction was stirred at room temperature for 20 h. Water (75 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic part was washed with water (3×50 mL) and brine (2×30 mL) and dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 20-30% ethyl acetate in hexane) to get 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(2,2-dimethyl-propyl)-amide (300) (310 mg, 86.27%) as an off-white sticky solid.
Reaction SMILES: C(O)C.C([O:6][C:7](=O)[CH2:8][CH2:9][N:10]([C:17]1[C:22]([NH2:23])=[CH:21][N:20]=[C:19]([Cl:24])[N:18]=1)[CH:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH3:16])C>C(O)(=O)C>[Cl:24][C:19]1[N:20]=[CH:21][C:22]2[NH:23][C:7](=[O:6])[CH2:8][CH2:9][N:10]([CH:11]3[CH2:15][CH2:14][CH2:13][CH:12]3[CH3:16])[C:17]=2[N:18]=1
Reactant: CCOC(=O)CCN(c1nc(Cl)ncc1N)C1CCCC1C
Solvent: CCO
Solvent: CC(=O)O
Product: CC1CCCC1N1CCC(=O)Nc2cnc(Cl)nc21
Yield: 74.5 %

Procedure:
A mixture of 50 mL of ethanol, 1 mL of acetic acid and 2.5 g of the (rac)-3-[(5-amino-2-chloro-pyrimidin-4-yl)-(2-methyl-cyclopentyl)-amino]-propanoic acid ethyl ester (V-57) prepared in the previous step was heated at reflux overnight, and then concentrated under reduced pressure. The residue was taken up in dichloromethane and washed successively with 10% sodium bicarbonate solution, and then water and dried over anhydrous sodium sulfate. The mixture was filtered and then concentrated under reduced pressure. Trituration of the residue with ether, provided 1.6 g of (rac)-2-chloro-9-(2-methyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-57).
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)=[O:20]>ClCCl>[CH3:18][S:19]([N:2]1[CH2:3][CH2:4][CH:5]2[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:1]1)=[O:20]
Reactant: CS(=O)Cl
Reactant: C1CCC2CNCCC2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)N1CCC2CCCCC2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.6 %

Procedure:
A solution of decahydroisoquinoline (1.16 g, 8.33 mmol) and triethylamine (1.1 g, 10.9 mmol) in anhydrous dichloromethane (20 mL) was cooled in a dry ice/acetone bath. The reaction mixture was treated with methanesulfinyl chloride (1.1 g, 11.2 mmol) dropwise. The reaction mixture was stirred and warmed to room temperature. After 5 h, the reaction mixture was filtered through Celite®. The filtrate was collected, washed with water (1×20 mL), dried (MgSO4) and concentrated in vacuo. Flash chromatography (SiO2, ethyl acetate eluant) afforded the product as a white solid (1.0 g, 60%) mp XX ° C.: 1H NMR (CDCl3, 600 MHz, δ) 3.39-3.34 (m, 1H, C1-H), 3.22-3.15 (m, 1H, C1-H), 2.90-2.85 and 2.73-2.68 (m, 1H, C-3H), 2.51-2.47 (m, 0.5H, C3-H) and 2.34 (t, 0.5H, J=11 Hz, C3-H), 2.51 (s, 1.5H, C1′-H) and 2.50 (s, 1.5H, C1′-H), 1.69-1.49 (m, 5H), 1.29-1.13 (m, 4H), 0.96-0.86 (m, 3H); 13C NMR (CDCl3, 125 MHz, δ) 54.3, 49.3, 48.4, 43.3, 42.4, 41.7, 41.6, 41.5, 39.14, 39.05, 38.95, 38.88, 33.2, 32.7, 32.6, 30.2, 30.1, 26.13, 26.12, 25.76, 25.71; ESIMS m/z 204.1 (5, 32S), 203.0 (13, 13C), 202.0 (base, MH+); ESIHRMS m/z 202.1260 (calculated for C10H20NOS 202.1260).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=1)=[O:10])[NH:2]2.[CH3:21][C:22]1[S:23][C:24]([C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1>>[CH3:21][C:22]1[S:23][C:24]([C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)=[C:25]([C:27]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:28])[N:26]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2c1OCCO2
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2[C@H](CNC(=O)c3cccc4c3OCCO4)C[C@@H]3C[C@@H]32)c1

Procedure:
prepared by reaction of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.38 min; [M+H]+=489.8.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:19])[CH:13]=[C:14]([NH2:18])[O:15][CH2:16][CH3:17])[CH3:10]>C(O)(C)C>[CH2:9]([O:11][C:12]([C:13]1[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]([C:12]([O:11][CH2:9][CH3:10])=[O:19])[C:14]([O:15][CH2:16][CH3:17])=[N:18][C:14]=1[NH2:18])=[O:19])[CH3:10]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)C=C(N)OCC
Solvent: CC(C)O
Product: CCOC(=O)C1=C(N)N=C(OCC)C(C(=O)OCC)C1c1ccccc1

Procedure:
Upon boiling a solution of 5.3 g of benzaldehyde and 15.9 g of 3-amino-3-ethoxyacrylic acid ethyl ester in 30 ml of alcohol for 12 hours, 2-amino-4-phenyl-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 119°C (isopropanol) is obtained.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[S:13]1[CH2:17][CH:16](C(O)=O)[NH:15][CH2:14]1>C1(C)C=CC=CC=1>[N:15]12[CH2:14][S:13][CH2:17][CH:16]1[CH2:3][CH:2]1[CH:11]2[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]1
Reactant: C=CCN(CC=O)C(=O)OCC
Reactant: O=C(O)C1CSCN1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CC3CSCN3C2C1

Procedure:
17.2 g (0.1 mol) of ethyl N-allyl-N-(2-oxoethyl)-carbamate are heated under reflux overnight with 13.5 g (0.1 mol) of thiazolidine-4-carboxylic acid in 300 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[C:14]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([N+]([O-])=O)=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17].C([O-])(=O)C.[Na+].[OH-].[Na+].Cl>O.C(O)C>[N+:24]([C:23]1[CH:22]=[C:21]2[C:20](=[C:15]([C:16]([OH:18])=[O:17])[CH:14]=1)[NH:1][C:2]1[CH:11]=[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[CH:4][C:3]=1[O:12]2)([O-:26])=[O:25]
Reactant: Nc1cc2ccccc2cc1O
Reactant: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc([N+](=O)[O-])cc2c1Nc1cc3ccccc3cc1O2
Yield: 73.7 %

Procedure:
304 mg (1.91 mmol) of 3-amino-2-naphthol, 477 mg (1.81 mmol) of methyl 2-chloro-3,5-dinitrobenzoate and 178 mg (2.17 mmol) of sodium acetate were suspended in a mixture of water (5 ml) with ethanol (10 ml) and heated under reflux for 7 hours. After adding 3 ml of a 2 N aqueous solution of sodium hydroxide thereto, the reaction mixture was heated under reflux for additional 2.5 hours and then brought back to room temperature. After adding 10 ml of 1 N hydrochloric acid thereto, the precipitate thus formed was recovered by filtration and washed successively with water, 1 N hydrochloric acid and ethanol to thereby give 430 mg of 3-nitro-12H-benzo[b]phenoxazine-1-carboxylic acid. Then this product was treated by the same methods as those of Production Example 23 and Example 13 to thereby give the title compound.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.CCN(C(C)C)C(C)C.Br[CH:27]([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(O)C>[CH2:31]([O:30][C:28](=[O:29])[CH:27]([N:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][N:7]=2)[CH2:14][CH2:13]1)[CH3:33])[CH3:32]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: CCOC(=O)C(C)Br
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
To a solution of 1-[5-(trifluoromethyl)pyrid-2-yl]piperazine (2.00 g, 8.65 mmol) in ethanol (25 mL) and DIPEA (3.3 mL, 19.0 mmol) was added ethyl 2-bromopropionate (1.20 mL, 9.51 mmol). The reaction mixture was heated to 70° C. After 14 hours, the reaction mixture was cooled to room temperature, concentrated and purified by flash chromatography on silica gel with elution using 50% ethyl acetate/hexanes to give 2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]propionic acid ethyl ester.