Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:13]([C:20]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:38])[CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][N:32]=3)[CH:25]=[N:26][CH:27]=2)=[O:21])=[CH:12]1)([CH3:10])[CH3:9])(C)(C)C>C1COCC1.Cl.O1CCOCC1>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]([NH:28][C:24]2[CH:25]=[N:26][CH:27]=[C:22]([C:20]([C:13]3[C:14]4[CH:15]=[N:16][CH:17]=[CH:18][C:19]=4[N:11]([C:8]([CH3:10])([CH3:9])[CH2:7][OH:6])[CH:12]=3)=[O:21])[CH:23]=2)=[O:38])=[N:32][CH:33]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cn3)c2)c2cnccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cn3)c2)c2cnccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
To a solution of N-(5-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-1H-pyrrolo[3,2-c]pyridine-3-carbonyl}-pyridin-3-yl)-2-(5-chloro-pyridin-2-yl)-acetamide (Preparation 8, 45 mg, 0.077 mmol) in THF (3 mL), 4M dioxane-HCl (0.4 mL) was added and stirred at room temperature for 18 hours. The reaction was evaporated in vacuo and purified by column chromatography on silica gel (gradient of MeOH: DCM 0:100 to 3:100) to afford the title compound as a yellow solid in 69% yield, 25 mg.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:29])[C:21]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>>[CH3:19][N:20]([CH3:29])[C:21]([CH:23]1[CH2:24][CH2:25][N:26]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN(C)C(=O)C1CCNCC1
Product: CN(C)C(=O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (Example 3) and piperidine-4-carboxylic acid dimethylamide using General Procedure B-3 yielded 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidine-4-carboxylic acid dimethylamide.
Reaction SMILES: C([O:9][C@H:10]1[C@H:14]([CH2:15][O:16]C(=O)C2C=CC=CC=2)[O:13][C@H:12]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:11]1[F:34])(=O)C1C=CC=CC=1.C(N)CCC>CO>[F:34][C@@H:11]1[C@@H:10]([OH:9])[C@H:14]([CH2:15][OH:16])[O:13][C@@H:12]1[N:25]1[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]1=[O:27]
Reactant: Cc1cn([C@H]2O[C@@H](COC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H]2F)c(=O)[nH]c1=O
Solvent: CCCCN
Solvent: CO
Product: Cc1cn([C@H]2O[C@@H](CO)[C@H](O)[C@H]2F)c(=O)[nH]c1=O

Procedure:
A solution of 23 (47 mg, 0.1 mmol) and n-butylamine (0.74 g, 1.0 mL, 10 mmol) in methanol (2 mL) was heated at reflux for 3 hours. The solution was evaporated to dryness and triturated with ethyl ether to afford a solid that was filtered, washed with ether and dried to afford 24 (20 mg, 0.077 mmol, 77% as a white solid: mp 188° C. (lit. value: mp 185-187° C., 184-185° C., 187-188° C. for the D-isomer); [α]D20=−93 (c 0.25 MeOH); (lit. value: [α]D20=−111 (c 0.23 MeOH), [α]D20=−122 (c.023 MeOH)); 1H-NMR (DMSO-d6) δ 11.0 (1H, bs, N—H, 7.58 (1H, s, C-H thymine), 6.09 (1H, dd, J=4.2 and J=15.6, H-1), 5.85 (1H, bs, OH), 5.10 (1H, bs, OH), 5.02 (1H, dt, J-4.0, J-3.8 and J-52.8, H-2), 4.22 (1H, dt, J-3.8, J-4.0 and J=20.3, H-3), 3.76 (1H, q, J=4.0 and J-9.5, H4), 3.69-3.57 (2H, m, H-5 and H-5′), 1.77 (3H, s, Thymine CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][C:13](=[O:15])[NH:12][C:11]3=[O:16])[C:9](=[O:17])[NH:8][C:5]2=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.O>[CH2:24]([N:12]1[C:13](=[O:15])[CH2:14][C:10]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:8][C:9]2=[O:17])[C:11]1=[O:16])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CC2(C(=O)N1)C(=O)Nc1ccc(Cl)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CC2(C(=O)Nc3ccc(Cl)cc32)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A stirred solution of the crude 5-chloro-1H-spiro[indole-3,3′-pyrrolidine]-2,2′,5′-trione, intermediate 9 (800 mg, 3.19 mmol) in anhydrous N,N-dimethylformamide (6 ml) was treated with potassium tert-butoxide (377 mg, 3.19 mmol). After stirring at ambient temperature for 40 min, benzyl bromide (0.38 ml, 3.19 mmol) was added. The mixture was stirred for 2 hours and left to stand overnight. The resultant mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude 1′-benzyl-5-chloro-1H-spiro[indole-3,3′-pyrrolidine]-2,2′,5′-trione which was purified by flash chromatography (silica) eluting with petroleum ether (40-60) containing an increasing amount (0 to 75%) of ethyl acetate. This gave 789 mg (73%) of a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:29][CH3:30])=[CH:7][C:8]=2[NH:12][C:13]2[C:14]([C:26]([OH:28])=O)=[CH:15][C:16]3[C:21]([C:22]=2[N+:23]([O-:25])=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:3]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[CH3:30][O:29][C:6]1[CH:5]=[C:4]2[O:3][C:2]([CH3:1])([CH3:31])[CH:11]=[CH:10][C:9]2=[C:8]2[C:7]=1[C:26](=[O:28])[C:14]1[CH:15]=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]3=[C:22]([N+:23]([O-:25])=[O:24])[C:13]=1[NH:12]2
Reactant: COc1cc(Nc2c(C(=O)O)cc3ccccc3c2[N+](=O)[O-])c2c(c1)OC(C)(C)C=C2
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(c3[nH]c4c([N+](=O)[O-])c5ccccc5cc4c(=O)c13)C=CC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
772 mg of the compound obtained in Step 4 are dissolved in 45 ml of anhydrous dichloromethane, and 3 ml of trifluoroacetic anhydride are added. After stirring for 5 minutes at ambient temperature, the reaction mixture is evaporated. The residue is taken up in a mixture of dichloromethane and saturated NaHCO3 solution. After extraction of the aqueous phase with dichloromethane, the combined organic phases are treated in conventional manner and then distilled, allowing the expected product to be isolated.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21].O>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([O:6][CH2:21][CH:20]=[CH2:19])=[O:5]
Reactant: Cc1cc(C)c(C(=O)O)c(C)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of 2,4,6-trimethylbenzoic acid (10 g, 61 mmol) in DMF (100 mL) were sequentially added potassium carbonate (17 g, 122 mmol) and allyl bromide (11 g, 91.5 mmol). The mixture was stirred at rt overnight before it was poured into water (˜1 L). The resulted precipitate was filtered and washed with water, then dried in vacuo to give allyl 2,4,6-trimethylbenzoate as a solid (10.2 g, 82%) which was nitrated and then reduced as shown for Example 14 (procedure B and C) to give allyl 3-amino-2,4,6-trimethylbenzoate.
Reaction SMILES: [CH:1]([N:4]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:17][CH:16]=3)=[N:12][CH:13]=[C:8]2[CH2:7][NH:6][C:5]1=[O:26])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.CC(C)([O-])C.[K+]>O1CCCC1>[CH:1]([N:4]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:19][CH:20]=3)=[N:12][CH:13]=[C:8]2[CH:7]=[N:6][C:5]1=[O:26])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)NCc2cnc(Nc3ccc(-n4cccn4)cc3)nc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1c(=O)ncc2cnc(Nc3ccc(-n4cccn4)cc3)nc21
Reaction time: 48 h
Yield: 77.4 %

Procedure:
Prepared from 150 mg (0.32 mmol) of 1-isopropyl-7-[4-(pyrazol-1-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, trifluoroacetic acid and 218 mg (1.94 mmol) of potassium tert-butoxide in 10 mL of tetrahydrofuran. The reaction mixture is stirred for 48 hours, 50 mg (0.44 mmol) of potassium tert-butoxide is added, and the reaction is continued for 72 hours. After the workup, the semi-solid is triturated in diethyl ether, and the powder is collected and dried to give 86 mg (73%) of the title compound: mp 243-247° C. (dec).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:28][CH2:27][C:20]4=[N:21][NH:22][C:23](=[O:26])[CH:24]([CH3:25])[N:19]4[C:18]=3[CH:29]=2)[CH2:11][CH2:10][N:9]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[CH2:1]([CH:8]1[CH2:13][CH:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:28][CH2:27][C:20]4=[N:21][NH:22][C:23](=[O:26])[CH:24]([CH3:25])[N:19]4[C:18]=3[CH:29]=2)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1C(=O)NN=C2COc3ccc(C4CCN(C(=O)OC(C)(C)C)C(Cc5ccccc5)C4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1C(=O)NN=C2COc3ccc(C4CCNC(Cc5ccccc5)C4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of tert-butyl 2-benzyl-4-(1-methyl-2-oxo-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)piperidine-1-carboxylate (0.147 g, 0.3 mmol) in DCM (2.5 mL) was added TFA (0.5 mL) and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo and EtOAc (2 mL) was added to the residue. The precipitate was collected by filtration and washed with EtOAc (1 mL) and petroleum ether (2 mL) to give 9-(2-benzylpiperidin-4-yl)-1-methyl-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (0.030 g, 20% yield for three steps) as a solid. LC/MS (Table 1, Method 4) Rt=1.651 min; MS m/z: 391 [M+H]+.
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:27])[CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][C:21]1([CH3:26])OCC[O:22]1.[OH-].[Na+]>O>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][C:21](=[O:22])[CH3:26])[N:5]([CH2:4][CH:3]([CH3:27])[CH3:2])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CC(C)Cn1c(CCC2(C)OCCO2)nc2c(N)nc3ccccc3c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)CCc1nc2c(N)nc3ccccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
Concentrated hydrochloric acid (0.80 mL, 9.3 mmol) was added to a stirred suspension of 1-(2-methylpropyl)-2-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.10 g, 3.10 mmol) in water (24 mL). A solution resulted and was stirred at room temperature for 30 minutes. The solution was adjusted to pH 12 with 20% aqueous sodium hydroxide. A white solid precipitated and was isolated by filtration, washed with water, and recrystallized from ethyl acetate to yield 0.6 g of 4-[4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]butan-2-one as a monohydrate as a white powder, mp 172-174° C. 1H NMR (300 MHz, DMSO-d6) δ 7.98 (d, J=8.1 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.41 (t, J=8.1 Hz, 1H), 7.26 (t, J=8.1 Hz, 1H), 6.41 (bs, 2H), 4.34 (d, J=7.5 Hz, 2H), 3.08 (bs, 41), 2.23 (s, 3H), 2.23-2.15 (m, 1H), 0.95 (d, J=6.9 Hz, 6H);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]2[C@H:16]([CH3:17])[C@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][C:13]2=[O:24])=[O:11])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])[C:10]([N:12]2[C@H:16]([CH3:17])[C@H:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:14][C:13]2=[O:24])=[O:11])=[CH:6][CH:7]=1
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)CCc1ccc(Cl)cc1
Reactant: CC(C)=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CC[C@@H](Cc1ccc(Cl)cc1)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Temperature: -78 °C
Yield: 36 %

Procedure:
To a cooled (−78° C.) solution of 3-[3-(4-chloro-phenyl)-propionyl]-4-(R)-methyl-5-(S)-phenyl-oxazolidin-2-one, 32, (500 mg, 1.46 mmol) in THF (15 mL) is added sodium bis(trimethylsilyl)-amide (1.75 mL, 1.0M solution in THF, 1.75 mmol). The resulting solution is stirred at −78° C. then 4-bromo-2-methyl-2-butene (0.20 mL, 1.75 mmol) is slowly added. The resulting solution is stirred at room temperature overnight, and the solvent removed under reduced pressure. The crude product is purified by preparative HPLC to afford 213 mg (36% yield) of the desired compound as a colorless oil. 1H NMR (CDCl3 300 MHz) δ 0.83 (d, J=6.6 Hz, 3H), 1.62 (s, 3H), 1.70 (s, 3H), 2.20–2.55 (m, 2H), 2.77–3.10 (m, 2H), 4.20–4.35 (m, 1H), 4.55–4.68 (m, 1H), 5.15–5.25 (m, 1H), 5.38 (d, J=7.2 Hz, 1H), 7.15–7.45 (m, 9H). MS (ESI) m/z 412 (M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:12])[C:9](O)=[O:10])=[CH:4][CH:3]=1.CCOC(C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([CH3:12])[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: C[C@@H](C(=O)O)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](CO)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
To a solution of 76C (95 mg, 0.42 mmol) in THF (3 mL) at 0° C., was added BH3 (1M in THF, 0.4 mL, 4 mmol). The mixture was stirred rt for 16 h. EtOAc (20 mL) was added, and the organic phase washed with 1M H3PO4, sat. NaHCO3 and brine, dried (Na2SO4), and concentrated to give 76D (90 mg, 100%). MS (ESI) m/z 197.0 (M−H2O+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19]2[S:20][C:21]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:3]1.[O:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:16][C:14]1[N:15]=[C:11]([C:9]([NH:8][C@H:7]2[CH2:6][CH2:5][N:4]([C:19]3[S:20][C:21]4[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)[CH2:3][C@H:2]2[NH:1][CH:36]2[CH2:37][CH2:38][O:33][CH2:34][CH2:35]2)=[O:10])[NH:12][C:13]=1[CH2:17][CH3:18]
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N)C3)sc12
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NC4CCOCC4)C3)sc12
Yield: 54 %

Procedure:
The same operation as in Example (77d) was performed using ethyl cis(±)-2-(3-amino-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained by the method described in Example (81e) (30 mg, 0.063 mmol), tetrahydro-4H-pyran-4-one (0.11 mL, 1.19 mmol) and sodium (triacetoxy)borohydride (238 mg, 1.12 mmol), to obtain 19.1 mg of the title compound as a white solid (54%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[NH:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[N:11]([C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1.84 g, prepared according to the procedure described in WO 96/31478 Step B page 94) in dry dichloromethane (50 mL) was treated with triethylamine (1.1 mL), then benzoyl chloride (0.91 mL). After stirring at room temperature for a further 5 hours the reaction mixture was treated with further dichloromethane (150 mL) and then washed twice with a saturated aqueous solution of sodium hydrogen carbonate (50 mL) and twice with brine (50 mL). The organic phase was then dried over magnesium sulfate and evaporated to give the title compound (2.58 g) as an orange oil, MS: 363 [MH]+. 1H NMR [(CD3)2SO]: δ 7.50–7.34 (m, 5H), 5.20–5.00 (s, 1H), 4.44–4.36 (m, 1H), 4.21–4.13 (m, 2H), 3.87–3.78 (m, 1H), 3.73–3.69 (bs, 1H), 3.30–3.20 (m, 2H), 2.98–2.90 (m, 1H), 1.45–1.38 (s, 9H) and 1.27–1.20 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].N1C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](/C=C\C(=O)O)C1(C)C
Yield: 99.2 %

Procedure:
2 g of 1,1-dimethylethyl(1R,cis)2,2-dimethyl-3[2-carboxyethynyl]-cyclopropane-carboxylate in 41 ml of ethyl acetate were hydrogenated in the presence of 0.38 g of 10% palladium hydroxide on barium sulfate and 0.4 ml of quinoline and the mixture was filtered. The filtrate was washed with 0.5N hydrochloric acid, then with water until neutral, dried and evaporated to dryness under reduced pressure to obtain 2 g of 1,1-dimethylethyl(1R,cis)2,2-dimethyl-3-[(Z)2-carboxyethenyl]-cyclopropane-carboxylate melting at 94° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[S:13])[NH2:12])=[CH:3]1.Br.[Br:15][CH2:16][C:17]([C:19]1[CH:20]=[NH+:21][CH:22]=[CH:23][CH:24]=1)=O>CN(C=O)C>[BrH:15].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[S:13][CH:16]=[C:17]([C:19]3[CH:20]=[NH+:21][CH:22]=[CH:23][CH:24]=3)[N:12]=2)=[CH:3]1
Reactant: O=C(CBr)c1ccc[nH+]c1
Reactant: Cn1cc(C(N)=S)c2ccccc21
Agent: Br
Solvent: CN(C)C=O
Product: Cn1cc(-c2nc(-c3ccc[nH+]c3)cs2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-Methylindole-3-thiocarboxamide (0.5 g) was dissolved in anhydrous DMF (5 ml). This solution was added to a stirred suspension of 3-bromoacetylpyridinium hydrobromide (1.1 g) in anhydrous DMF (2 ml). This was stirred for 10 minutes at room temperature. The title compound was isolated by filtration and was washed thoroughly with ether, 0.5 g. δH (360 MHz, DMSO-d6) 3.91 (3H, s, NCH3), 7.2-7.4 (2H, m, H-5 and H-6), 7.58 (1H, d, J=7.4 Hz, H-7), 8.03 (1H, dd, J=5.5, 8.1 Hz, H-5" β-pyr), 8.26 (1H, s, H-5' thiazole), 8.36 (1H, d, partially buried, H-4), 8.38 (1H, s, H-2), 8.83 (1H, mc, H-4" γ-pyr), 8.99 (1H, d, J=8.2 Hz, H-6" α-pyr), 9.47 (1H, mc, H-2" α-pyr); m/z 291 (M+, 100%), 135 (30).
Reaction SMILES: [F:1][CH2:2][C:3]([OH:5])=O.C(Cl)CCl.[I:10][C:11]1[N:15]2[CH:16]=[CH:17][C:18]([C:20]([NH:22][NH2:23])=[O:21])=[CH:19][C:14]2=[N:13][CH:12]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][CH2:2][C:3]([NH:23][NH:22][C:20]([C:18]1[CH:17]=[CH:16][N:15]([C:11]([I:10])=[CH2:12])[C:14](=[NH:13])[CH:19]=1)=[O:21])=[O:5]
Reactant: NNC(=O)c1ccn2c(I)cnc2c1
Reactant: O=C(O)CF
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: C=C(I)n1ccc(C(=O)NNC(=O)CF)cc1=N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of fluoroacetic acid (52 mg, 0.66 mmol) in CH2Cl2 (5 ml) was added EDC (127 mg, 0.66 mmol) and DMAP (5 mg, catalytic) and the reaction mixture stirred at room temperature for 15 min. 3-Iodo-imidazo[1,2-a]pyridine-7-carboxylic acid hydrazide (prepared as described in Example 329 steps a-c) (100 mg, 0.33 mmol) was added and the reaction mixture stirred at room temperature for 18 h. The reaction mixture was filtered, the precipitate washed with Et2O and dried to afford a crude product which was used directly in the next reaction (101 mg). MS: [M+H]+=363.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:12]([CH3:14])[CH3:13])[N:5]=[C:6]([O:10][CH3:11])[CH:7]([CH3:9])[N:8]=1.C([Li])CCC.IC[C@@H:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][CH3:24]>O1CCCC1>[CH:12]([C@@H:4]1[C:3]([O:2][CH3:1])=[N:8][C@@H:7]([CH2:9][C@@H:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][CH3:24])[C:6]([O:10][CH3:11])=[N:5]1)([CH3:14])[CH3:13]
Reactant: CC[C@@H](CI)c1ccccc1
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[C@@H](C[C@@H]1N=C(OC)[C@@H](C(C)C)N=C1OC)c1ccccc1
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A solution of (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-methylpyrazine (4.25 g, 23.1 mmol) in tetrahydrofuran (30 ml) was cooled to −78° C., then n-butyllithium (1.6 M in hexane, 15.1 ml, 24.2 mmol) was added and the mixture was stirred for 1 hour. A solution of ((R)-1-iodomethyl-propyl)-benzene (6.30 g, 24.2 mmol) in tetrahydrofuran (30 ml) was added dropwise over 30 min and the mixture was stirred overnight while being allowed to warm slowly from −70° C. to room temperature. The reaction was quenched by addition of saturated aqueous ammonium chloride solution and the mixture was extracted with ether. The organic layer was separated, washed with saturated brine, then dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptane/EtOAc) to yield a light yellow oil (4.69 g, 64%); MS (ISP): 317.0 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([S:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13]O)[CH:6]=[CH:7][C:8]=1[Cl:9].S(Cl)(Cl)=O.[CH:25](Cl)(Cl)[Cl:26]>>[F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([Cl:9])=[CH:7][C:6]2[CH:25]([Cl:26])[CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[S:10][C:5]=2[CH:4]=1
Reactant: ClC(Cl)Cl
Reactant: OCc1ccccc1Sc1ccc(Cl)c(C(F)(F)F)c1
Solvent: O=S(Cl)Cl
Product: FC(F)(F)c1cc2c(cc1Cl)C(Cl)Cc1ccccc1S2
Reaction time: 12 h

Procedure:
A mixture of the alcohol from the preceding experiment (3.3 g) and thionyl chloride (1.2 ml) is allowed to stand at room temperature for 12 hours and then heated under a reflux condenser in a steam-bath for 1 hour. The reaction mixture is cooled, dissolved in chloroform and the solution washed with water and dried over calcium chloride. Evaporation of the solvent affords crystalline 7-trifluoromethyl-8,10-dichloro-10,11-dihydrodibenzo(b,f)thiepine, melting at 100°-102° C. after crystallization from acetone.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[CH2:22]([O:29][C@H:30]1[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:32]([CH2:42]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(N(C)C)=O>[CH2:22]([O:29][C@H:30]1[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:32]([CH2:42][O:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:31]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2C[C@@H](OCc3ccccc3)CN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccccc1CCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)CC1COc1ccccc1CCc1ccccc1
Yield: 81.3 %

Procedure:
Following a procedure similar to that described in Example 40(a), 200 mg of 2-(2-phenylethyl)phenol (prepared as described in Preparation 19), 124 mg of potassium t-butoxide and 500 mg of (4R)-4-benzyloxy-1-t-butoxycarbonyl-2-(p-toluenesulfonyloxymethyl)pyrrolidine were reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 40(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 400 mg (yield 81%) of the title compound as a colorless oil.