Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:5]([N:7]1[CH2:24][CH2:23][CH2:22][C@:9]2([C:13](=[O:14])[N:12]([CH3:15])[CH2:11][C@H:10]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8]1)=[O:6].[C:33]1(O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:15][N:12]1[CH2:11][C@@H:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@:9]2([CH2:22][CH2:23][CH2:24][N:7]([C:5](=[O:6])[C@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:3][CH2:2][O:1][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:8]2)[C:13]1=[O:14]
Reactant: Oc1ccccc1
Reactant: CN1C[C@@H](c2ccccc2)[C@@]2(CCCN(C(=O)[C@@H](CCO)NC(=O)OC(C)(C)C)C2)C1=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1C[C@@H](c2ccccc2)[C@@]2(CCCN(C(=O)[C@@H](CCOc3ccccc3)NC(=O)OC(C)(C)C)C2)C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Tert-butyl (R)-4-hydroxy-1-((4S,5R)-2-methyl-1-oxo-4-phenyl-2,7-diazaspiro[4.5]decan-7-yl)-1-oxobutan-2-ylcarbamate (111 mg; 0.249 mmol) was solubilised in THF (2.5 ml). Phenol (24 mg; 0.249 mmol) was added followed by triphenylphosphine (98 mg; 0.374 mmol). The solution was cooled to 0° C. and diisopropyl azodicarboxylate (0.073 ml; 0.374 mmol) was added. The reaction mixture was warmed to RT slowly and stirred overnight. The solution was concentrated in vacuo and purified by chromatography on silica eluting with 0-10% MeOH in DCM with ammonia. The compound eluted with triphenylphospine oxide and was used crude in the next step.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][O:13]2)[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[NH:8]1[CH2:12][CH2:11][C:10]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][O:13]2)[CH2:9]1
Reactant: c1ccc(CN2CCC3(C2)OCc2ccccc23)cc1
Agent: [Pd]
Solvent: CO
Product: c1ccc2c(c1)COC21CCNC1
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of 1′-benzyl-3H-spiro[2-benzofuran-1,3′-pyrrolidine] (200 mg, 0.0008 mol) in methanol (10 mL) was added Pd/C (150 mg), and the suspension was hydrogenated under H2 (50 psi) overnight. The mixture was filtered and then concentrated to give the desired compound (110 mg, 92% yield). MS (ESI): 176.1 (M+H+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[N:12][CH:13]=1.B1([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)C2CCCC1CCC2>C1COCC1.O.C1COCC1.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>[CH2:36]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[N:12][CH:13]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Cc3ccccc3)cn2)CC1

Procedure:
A mixture of K2CO3 (6 gm, 43.5 mmol, 3 equiv) and Pd(PPh3)4 (1 gm, 0.86 mmol) were stirred at room temperature in 20 mL THF/water (1:1) for 30 minutes. Tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (5 gm, 14.5 mmol, 1 equiv) was then added with B-benzyl-9-BBN (2 equiv, 49 ml of a 0.5 M solution in THF). The resulting mixture was heated with stirring under argon atmosphere in an oil bath adjusted at 100-110° C. until the reaction had reached completion, as monitored by TLC. The reaction mixture was extracted with CHCl3 (3×200 mL). The combined organic layers were then dried with anhydrous Na2SO4. Chloroform was evaporated under reduced pressure and the residue was purified using flash column chromatography (initially with 4:1 hexane/ethyl acetate and finally with 1:1 hexane/ethyl acetate). Tert-butyl 4-(5-benzylpyrimidin-2-yl)piperazine-1-carboxylate was obtained as a yellow solid (3.8 gm, 74% yield); mp: 121-123° C. 1H-NMR (DMSO-d6): δ 1.47 (s, 9H), 3.47 (t, J=4.68 Hz, 4H), 3.75 (t, J=4.68 Hz, 4H), 3.78 (s, 2H), 7.14-7.29 (m, 5H), 8.16 (s, 2H). 13C-NMR (DMSO-d6): δ 28.4, 35.61, 43.70, 79.92, 122.29, 126.41, 128.51, 128.66, 140.02, 154.84, 157.87, 160.69. MS: calcd 354.21 for C20H26N4O2 [M]+. found, 355.21 [M+1]+. b) 3.7 gm of the obtained product from step a was then deprotected using HCl/MeOH as described above in the preparation of 1. As a result, compound 2 was obtained as a pale yellow solid (2.2 gm, 80% yield); mp: 108-110° C. 1H-NMR (DMSO-d6): δ 1.89 (s, 1H), 2.93 (t, J=4.8 Hz, 4H), 3.76 (t, J=4.8 Hz, 4H), 3.79 (s, 2H), 7.17-7.29 (m, 5H), 8.18 (s, 2H). 13C-NMR (DMSO-d6): δ 35.59, 44.96, 45.92, 121.79, 126.34, 128.48, 128.6, 140.1, 157.8, 160.5. MS: calcd 254.15 for C15H18N4 [M]+. found, 255.15 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]([CH2:14][N:15]([CH3:17])[CH3:16])=[C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:24][CH3:25])[CH:10]=2)[C:5]1=[O:26].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(Cl)Cl>CCOCC>[CH3:16][N:15]([CH2:14][C:13]1[N:4]([CH2:3][CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36])[C:5](=[O:26])[C:6]2[C:11]([C:12]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[CH:10][C:9]([O:24][CH3:25])=[CH:8][CH:7]=2)[CH3:17]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(=O)n(CCN)c(CN(C)C)c(-c3ccccc3)c2c1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(=O)n(CCNS(C)(=O)=O)c(CN(C)C)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.5 %

Procedure:
A solution of 116 (50 mg, 0.118 mmol), triethylamine (66 μL, 0.472 mmol), methanesulfonyl chloride (12 μL, 0.153 mmol) and methylene chloride (250 μL) were combined under Ar and stirred at room temperature 24 h. Added methylene chloride and washed the contents of the reaction flask with sat. sodium bicarbonate. Dried the organic layer with sodium sulfate (anh.), filtered then rotary evaporated the filtrate. Trituration of the resulting solid with ether gave 117 as a white solid (35 mg, 0.082 mmol, 69.1%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([N:18]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:19]([C:23]1([OH:29])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[C:20]([OH:22])=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[C:38]1[C:43]([F:44])=[C:42]([F:45])[CH:41]=[CH:40][C:39]=1[N+:46]([O-:48])=[O:47].OS([O-])(=O)=O.[K+]>C1COCC1.O>[CH2:30]([N:18]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:19]([C:23]1([O:29][C:38]2[C:43]([F:44])=[C:42]([F:45])[CH:41]=[CH:40][C:39]=2[N+:46]([O-:48])=[O:47])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[C:20]([OH:22])=[O:21])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: O=C(O)C(N(Cc1ccccc1)Cc1ccccc1)C1(O)CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(N(Cc1ccccc1)Cc1ccccc1)C1(Oc2c([N+](=O)[O-])ccc(F)c2F)CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 31.8 %

Procedure:
Potassium bis(trimethylsilyl) amide, 1 M solution in THF (4.22 mL, 4.22 mmol, Eq: 3.00), was added to a solution of 2-(dibenzylamino)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-acetic acid (0.5 g, 1.41 mmol, Eq: 1.00) in THF (10 mL) at RT and the mixture stirred for 15 min. The mixture was cooled to 0° C., 2,3,4-trifluoronitrobenzene (1.25 g, 0.83 mL, 7 mmol, Eq: 5.00) was added and the mixture stirred at 0° C. for 45 min. The mixture was diluted with H2O at 0° C. and was warmed to RT. The pH was adjusted to ˜2-3 with sat KHSO4, the mixture extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, concentrated and the residue purified by flash chromatography to afford 2-(dibenzylamino)-2-(4-(5,6-difluoro-2-nitrophenoxy)tetrahydro-2H-pyran-4-yl)-acetic acid (0.23 g, 32% yield). MS m/z 513.0 (MH+)
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)=[CH:9][C:8]=2[C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:6][CH2:5]1)[CH3:2].[OH-].[Na+].O.CC#N>C(O)C.O1CCCC1>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:19][CH:20]=3)=[CH:9][C:8]=2[C:26]([CH3:27])([CH3:29])[CH3:28])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC1(c2ccc(C#Cc3ccc(CC(=O)OC)cc3)cc2C(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CCO
Product: CCOC1(c2ccc(C#Cc3ccc(CC(=O)O)cc3)cc2C(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 71.5 %

Procedure:
Using General Procedure I; a solution of methyl {4-[4-(1-ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-phenyl}-acetate (Compound 104, 100.0 mg, 0.26 mmol) in ethanol (4 mL) and tetrahydrofuran (4 mL) was treated with NaOH (240.0 mg, 6.0 mmols, 3.0 mL of a 2N aqueous solution) and stirred at 50° C. for 4 h. Work-up and isolation by HPLC (Partisil 10-pac, 10% H2O/CH3CN) afforded 70.0 mg (73%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](F)[N:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[OH-:23].[K+]>C(O)(C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[N:16]=[C:17]([OH:23])[CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cccc(F)n1
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cccc(O)n1

Procedure:
The title compound, light yellow solid, MS: m/e=310.1, 312.0 (M+H), was prepared in accordance with the general method of example 1a from 2-[4-(3-chloro-phenylethynyl)-2-methyl-imidazol-1-yl]-6-fluoro-pyridine and KOH in tert-butanol.
Reaction SMILES: NC(CCCCCCCCC(N)C(C)C)C(C)C.[CH:19]1([CH:26]2[CH2:37][CH:36]=[CH:35][CH2:34][CH2:33][CH:32]=[CH:31][CH2:30][CH:29]([CH:38]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[N:28]=[N:27]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[NH2:27][CH:26]([CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH:29]([NH2:28])[CH:38]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: C1=CCC(C2CCCCCC2)N=NC(C2CCCCCC2)CC=CCC1
Agent: CC(C)C(N)CCCCCCCCC(N)C(C)C
Product: NC(CCCCCCCCC(N)C1CCCCCC1)C1CCCCCC1

Procedure:
The procedure described in (a) is repeated, starting from 106 g (0.3 mole) of 3,12-dicycloheptyl-1,2-diaza-1,5,9-cyclododecatriene (diastereoisomer mixture) and using correspondingly reduced amounts of catalyst and solvent, affording after purification by chromatography 63 g (58% of theory) of 1,10-diamino-1,10-dicycloheptyldecane as a colourless oil [nD20 =1.5018; IR spectrum (liquid) includes bands at 3390, 3310, 3618 cm-1 ]. PG,21
Reaction SMILES: [Na].[CH3:2][O:3][CH:4]([O:12]C)[C:5](=[CH:10]O)[C:6](OC)=O.Cl.[C:15]([NH:19][NH2:20])([CH3:18])([CH3:17])[CH3:16].O>C(O)C>[C:15]([N:19]1[CH:10]=[C:5]([C:4]([O:3][CH3:2])=[O:12])[CH:6]=[N:20]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)NN
Reactant: COC(=O)C(=CO)C(OC)OC
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cnn(C(C)(C)C)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 67.6 %

Procedure:
8.51 g of methyl 2-(dimethoxymethyl)-3-hydroxyacrylate sodium salt of was suspended in 80 ml of ethanol, and 8.09 g of t-butylhydrazine hydrochloride was then added. The mixture was stirred at 60° C. for 4 hours and then cooled to room temperature. After 50 ml of water was added, the reaction mixture was concentrated to 50 ml under reduced pressure. The concentrated solution was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was recrystallized from hexane to obtain 5.26 g of methyl 1-t-butyl-pyrazole-4-carboxylate.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]([OH:13])=[O:12])[CH2:7]1.[CH3:14]O>>[NH2:5][C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7]1
Reactant: N[C@H]1CC[C@@H](C(=O)O)C1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1CC[C@H](N)C1
Yield: 87 %

Procedure:
Thionyl chloride (1.30 ml, 18.2 mmol) was added to a stirred solution of (1R,3S)-3-amino cyclo pentyl carboxylic acid (2.00 g, 12.1 mmol) in MeOH (20 ml) and refluxed for 3 h. The reaction mixture was concentrated under reduced pressure and co-distilled with toluene to afford 1.9 g (87%) of (1R,3S)-methyl 3-aminocyclopentanecarboxylate as off-white solid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[CH2:24][CH:23]([CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:28][CH2:27]3)[C:21](=[O:22])[C:16]2=[CH:17][C:18]=1[O:19][CH3:20]>C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[CH2:24][CH:23]([CH2:25][CH:26]3[CH2:27][CH2:28][N:29]([CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:30][CH2:31]3)[C:21](=[O:22])[C:16]2=[CH:17][C:18]=1[O:19][CH3:20].[C:6]([CH:4]([CH:2]([C:1]([O-:10])=[O:9])[OH:3])[OH:5])([O-:8])=[O:7]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Temperature: 25 °C

Procedure:
Tartaric acid (1.5 g, dissolved in 35 ml of absolute ethanol) is slowly added to a solution of Donepezil (3.79 g) in ethyl acetate (70 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 169.6° C.
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([F:24])[CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[F:25][C@H:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28]O>>[CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:28][CH2:27][C@H:26]([F:25])[CH2:30][CH2:31][CH3:32])=[C:19]([F:24])[CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)c(F)c2)nc1
Reactant: CCC[C@@H](F)CCO
Product: CCCCCCCCCCc1cnc(-c2ccc(OCC[C@H](F)CCC)c(F)c2)nc1
Yield: 28.9 %

Procedure:
The titled compound was synthesized from 5-decyl-2-(3-fluoro-4-hydroxyphenyl)pyrimidine and (R)-3-fluorohexanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH3:14])=[C:4]([CH3:15])[CH:3]=1.[C:16](N1C=CN=C1)(N1C=CN=C1)=[S:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH3:14])[C:16]2=[S:17])=[C:4]([CH3:15])[CH:3]=1
Reactant: CCNCCCNc1ccc(Cl)cc1C
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCN1CCCN(c2ccc(Cl)cc2C)C1=S

Procedure:
The cyclization of the crude diamine of Step D was carried out with one equivalent of 1,1′-thiocarbonyldiimidazole in refluxing dioxane under nitrogen for one hour. Subsequently, two equivalents of para-toluenesulfonic acid hydrate were added and the mixture was refluxed for 48 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (100 mL). The solution was washed with water, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (on Merck-60 silica gel) eluting with 10-25% petroleum ether/ethyl acetate. The title compound was obtained as a white solid (4.4 g, 52%), m.p. 116-118° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18](N)=[O:19])=[CH:16][C:10]=3[C:9](=[O:22])[CH2:8][C:7]=2[CH:23]=1.Br.C(O)(=[O:27])C>CCCCCC>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18]([OH:19])=[O:27])=[CH:16][C:10]=3[C:9](=[O:22])[CH2:8][C:7]=2[CH:23]=1
Reactant: CC(=O)O
Reactant: COc1ccc2c(c1)CC(=O)c1cc(C(C)C(N)=O)ccc1S2
Agent: Br
Solvent: CCCCCC
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1cc(O)ccc1S2
Reaction time: 3 h
Yield: 82 %

Procedure:
A mixture of 130 mg of 2-(10,11-dihydro-8-methoxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide, 20 ml of hydrobromic acid and 8 ml of acetic acid was refluxed with stirring for 3 hours. The solvent was distilled off to obtain a residue, which was extracted with chloroform. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain crude crystals, which were recrystallized from ethyl acetate--n-hexane to obtain 102 mg (yield: 82%) of 2-(10,11-dihydro-8-hydroxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as a light yellow powder having a melting point of 216°-217° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][C:10]([O:12][C:13]3[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[CH:11][C:6]=2[C:5](=[O:20])[N:4]([CH2:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:3]1=[O:31].[Li+].CC([N-]C(C)C)C.[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]=[O:46])=[CH:43][CH:42]=1>C1COCC1.CC(=O)OCC.O>[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]([OH:46])[C:11]2[C:6]3[C:5](=[O:20])[N:4]([CH2:21][CH2:22][CH2:23][O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:3](=[O:31])[N:2]([CH3:1])[C:7]=3[N:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:43][CH:42]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1ccc(Oc2cnc3c(c2)c(=O)n(CCCOC2CCCCO2)c(=O)n3C)cn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Oc2cnc3c(c2C(O)c2ccc(Cl)cc2)c(=O)n(CCCOC2CCCCO2)c(=O)n3C)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 6.7 %

Procedure:
To a solution of 1-methyl-6-((6-methylpyridin-3-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (450 mg, 1.06 mmol) in THF (8 mL) at −78° C. was added LDA (2M in THF, 2.11 mL, 4.24 mmol) dropwise. The reaction was stirred at −78° C. for 1 h. then a solution of 4-chlorobenzaldehyde (296.6 mg, 2.11 mmol) in THF (2 mL) was added dropwise. The reaction was stirred for 30 min at −78° C. then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1 to 1:1) to give 5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-6-((6-methylpyridin-3-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (40 mg, 6.7% yield) as an oil. LCMS: MH+ 567 and TR=1.400 min.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH2:27]([NH2:29])[CH3:28]>C(O)C>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:29][CH2:27][CH3:28])[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CCN
Solvent: CCO
Product: CCNc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Temperature: 25 °C

Procedure:
To a 10 mL microwave vial equipped with stir bar, septum cap and nitrogen inlet were added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (23 mg, 0.062 mmol) and ethanol (1 mL). Added next to the stirring suspension was ethylamine (0.100 mL, 1.230 mmol) via syringe at once. The sealed reaction mixture was irradiated (microwave) at 110° C. for 40 min, followed by addition of 0.1 mL ethylamine and further irradiation for 7 hr at 130° C. After cooling to room temperature, about 50% of the volatiles were removed by a stream of nitrogen. The reaction mixture was diluted with water (20 mL) and stirred for 10 min. The mixture was then filtered and the collected solid washed with water. The solid was dried in vacuum oven at 50° C. for 18 h, to afford the title compound as 0.17 g (71%). LCMS E-S (M+H)=383.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.07 Hz, 3 H), 1.43 (d, J=6.57 Hz, 6 H), 2.12 (s, 3 H), 2.21 (s, 3 H), 3.35-3.39 (m, 2 H), 4.31 (d, J=5.05 Hz, 2 H), 4.89-5.01 (m, 1 H), 5.89 (s, 1 H), 6.61 (s, 1 H), 7.18 (t, J=5.31 Hz, 1 H), 7.83 (s, 1 H), 8.44 (t, J=5.05 Hz, 1 H), 11.55 (br. s., 1 H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[N:5]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:4]=1.[NH:27]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][N:5]2[C:6]([C:8]3[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=3)=[CH:7][C:3]([CH2:2][N:27]3[CH2:33][CH2:32][CH2:31][N:30]([CH2:2][C:3]4[CH:7]=[C:6]([C:8]5[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=5)[N:5]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)[N:4]=4)[CH2:29][CH2:28]3)=[N:4]2)[CH:22]=1
Reactant: COc1cc(-c2cc(CCl)nn2Cc2cccnc2)cc(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc(-c2cc(CN3CCCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)n(Cc5cccnc5)n4)CC3)nn2Cc2cccnc2)cc(OC)c1OC

Procedure:
3-Chloromethyl-1-(3-pyridylmethyl)-5-(3,4,5-trimethoxyphenyl)pyrazole (110 mg) and homopiperazine (13 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [CH3:1][O:2][N:3]([C:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:4]1[NH:5][C:6](=[O:31])[C:7]2[N:8]=[CH:9][N:10]([C@@H:13]3[O:18][C@H:17]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@@H:15]([OH:16])[C@@:14]3([C:29]#[CH:30])[F:28])[C:11]=2[N:12]=1.C1COCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:67]1[CH:72]=[CH:71][CH2:70][CH2:69][CH2:68]1>C(Cl)Cl>[CH3:1][O:2][N:3]([C:32]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:4]1[NH:5][C:6](=[O:31])[C:7]2[N:8]=[CH:9][N:10]([C@@H:13]3[O:18][C@H:17]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:22])[CH3:23])[C@@H:15]([O:16][CH:68]4[CH2:69][CH2:70][CH2:71][CH2:72][O:67]4)[C@@:14]3([C:29]#[CH:30])[F:28])[C:11]=2[N:12]=1
Reactant: C#C[C@@]1(F)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]1n1cnc2c(=O)[nH]c(N(OC)C(c3ccccc3)(c3ccccc3)c3ccccc3)nc21
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#C[C@@]1(F)[C@H](OC2CCCCO2)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]1n1cnc2c(=O)[nH]c(N(OC)C(c3ccccc3)(c3ccccc3)c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 13 (0.8 mmol), in and THF (20 ml/mmol), at room temperature, was added p-toluen sulfonic acid (0.12 mmol) and dihydropyran (2 ml/mmol). The reaction mixture was stirred at room temperature for 3 days and neutralized with TEA. The mixture was diluted with DCM, washed twice with H2O. The organic phase was dried over Na2SO4, filtered and evaporated. The crude material was purified by silica gel chromatography (DCM/MeOH) to yield the title compound. Molecular Formula C43H52FN5O6Si. Scan ES+ 780 (M+H)+