Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@:2]1([C:20](OC)=[O:21])[CH2:11][C:10]2([S:15][CH2:14][CH2:13][S:12]2)[C:9]2[C:4](=[C:5]([O:18][CH3:19])[CH:6]=[CH:7][C:8]=2[O:16][CH3:17])[CH2:3]1.[BH4-].[Na+]>O1CCCC1>[OH:1][C@@:2]1([CH2:20][OH:21])[CH2:3][C:4]2[C:9](=[C:8]([O:16][CH3:17])[CH:7]=[CH:6][C:5]=2[O:18][CH3:19])[C:10]2([S:12][CH2:13][CH2:14][S:15]2)[CH2:11]1
Reactant: COC(=O)[C@]1(O)Cc2c(OC)ccc(OC)c2C2(C1)SCCS2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(OC)c2c1C[C@@](O)(CO)CC21SCCS1

Procedure:
Reduction of methyl (S)-1',2',3',4'-tetrahydro-2'-hydroxy-5',8'-dimethoxyspiro[1,3-dithiolane-2,4'-naphthalene]-2'-carboxylate [prepared as described in Example 4(ii)] with sodium borohydride in tetrahydrofuran in a manner analogous to that described in Example 5(i) gave (S)-1',2',3',4'-tetrahydro-3'-hydroxy-3'-hydroxymethyl-5',8'-dimethoxyspiro[1,3-dithiolane-2,1'-naphthalene] in the form of a colourless gum which was used directly in the next step.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH3:10][CH:11]([NH2:13])[CH3:12].CCN(CC)CC>>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:13][CH:11]([CH3:12])[CH3:10])[C:7]=1[NH2:8]
Reactant: CC(C)N
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CCN(CC)CC
Product: CC(C)Nc1ncnc(Cl)c1N
Temperature: 25 °C

Procedure:
4,6-Dichloropyrimidin-5-amine (492 mg, 3 mmol), propan-2-amine (284 μl, 3.3 mmol) and Et3N (836 μl, 6 mmol) were combined and heated at reflux. The mixture was refluxed for 5 days and each day additional isopropylamine (0.77 mL, 9 mmol) was added. The reaction mixture was cooled to room temperature, concentrated, slurried in water, filtered, rinsed with additional water and dried under reduced pressure to provide the title compound 52A as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 7.72 (1H, s), 6.53 (1H, d), 5.02 (2H, s), 4.20 (1H, octet), 1.18 (6H, d).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([O:22][CH3:23])[CH:18]=3)[CH:13]=2)([OH:11])[CH:8]([CH3:10])[CH3:9])=[CH:5][N:6]=1.C([O-])(=O)C.[Na+]>C(O)C.[Pd]>[CH3:23][O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:24][CH3:25])[CH:13]=[C:12]([C:7]([C:4]1[S:3][CH:2]=[N:6][CH:5]=1)([OH:11])[CH:8]([CH3:10])[CH3:9])[CH:21]=[CH:20]2
Reactant: COc1cc2ccc(C(O)(c3cnc(Cl)s3)C(C)C)cc2cc1OC
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc2ccc(C(O)(c3cncs3)C(C)C)cc2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a stirred solution of alcohol 1 (0.07 g, 0.18 mmol) in ethanol (10 mL) were added sodium acetate (10 mg, 0.12 mmol) followed by addition of 10% Pd/C (60 mg) at RT under inert atmosphere. The reaction mixture was stirred at RT for 2 h under H2 atmosphere (30 psi). Progress of reaction was monitored by TLC. The reaction mixture was filtered through a pad of celite and celite bed was washed with ethanol (2×10 mL). The filtrate was concentrated under reduced pressure to afford 2 (50 mg, 0.15 mmol, 78%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.75 (s, 1H), 7.88 (s, 1H), 7.85 (s, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.13 (s, 1H), 7.09 (s, 1H), 3.99 (s, 6H), 2.84-2.78 (m, 1H), 1.06 (d, J=6.5 Hz, 3H), 0.87 (d, J=6.5 Hz, 3H). Mass: m/z: 344 [M+1]. HPLC: 99.65%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[I+].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 80 °C
Yield: 59 %

Procedure:
A mixture of 3 g (14.78 mmol) of 5-bromo-2-nitropyridine, 5.5 g (29.56 mmol) of tert-butyl 1-piperazinecarboxylate, 5.46 g (14.78 mmol) of tetra-butylammonium iodine and 4.1 g (29.56 mmol) of potassium carbonate were placed in a flask. Dimethylsulfoxide (45 mL) is added and heat up to 80° C. for 24 hours. After cooling to room temperature, the precipitate is filtered and washed with ethyl acetate. Excess amount of water is added and extracted 4×. Dried with sodium sulfate and evaporated to give 2.7 g (59% yield) as a yellow solid. MS (ESI) m/z 309.1(M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([OH:20])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH2:21][C:22]([NH:24][CH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)=[O:23].Br[CH:40]([CH3:42])[CH3:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH:40]([CH3:42])[CH3:41])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH2:21][C:22]([NH:24][CH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)=[O:23]
Reactant: CC(C)Br
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CCC2
Product: COc1ccc(CC2c3cc(OC(C)C)c(OC)cc3CCCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide with 2-bromopropane.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].CC(C)([O-])C.[K+].CC1C=CC([C:19]2[C:20]([F:41])=[C:21]([CH:25]=[C:26]([Cl:40])[C:27]=2[S:28][C:29]2[CH:30]=[N:31][C:32]([O:36][CH:37]([CH3:39])[CH3:38])=[C:33]([Cl:35])[CH:34]=2)[C:22]([O-])=[O:23])=CC=1>C1COCC1>[Cl:40][C:26]1[C:27]([S:28][C:29]2[CH:30]=[N:31][C:32]([O:36][CH:37]([CH3:39])[CH3:38])=[C:33]([Cl:35])[CH:34]=2)=[CH:19][C:20]([F:41])=[C:21]([CH:25]=1)[C:22]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:23]
Reactant: Cc1ccc(-c2c(F)c(C(=O)[O-])cc(Cl)c2Sc2cnc(OC(C)C)c(Cl)c2)cc1
Reactant: CS(N)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)Oc1ncc(Sc2cc(F)c(C(=O)NS(C)(=O)=O)cc2Cl)cc1Cl
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 13.2 %

Procedure:
To a suspension of methanesulfonamide (93.4 mg, 0.98 mmol) in THF (2 mL) at room temperature was added potassium tert-butoxide (119 mg, 1.06 mmol) in one portion with stirring under nitrogen for 15 minutes. 4-Methylphenyl-5-chloro-4-[(5-chloro-6-isopropoxypyridin-3-yl)thio]-2-fluorobenzoate (Preparation 224, 352 mg, 0.75 mmol) was added as a solution in THF (2 mL). The mixture was then heated at 60° C. for 3 hours and then left at room temperature for 18 hours. The solvent was concentrated in vacuo and the residue was partitioned between EtOAc (10 mL) and water (5 mL). The organic layer was separated and then washed with 1M NaOH (5 mL), 2M HCl (5 mL), saturated aqueous brine (5 mL), dried over MgSO4 filtered and evaporated. The residue was triturated with acetone/heptane (1:9) to afford a white solid which was filtered and washed with heptane to yield the title compound (45 mg, 13%) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:9])[CH2:8][CH2:7]1)=[O:5].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]1([NH:9][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[Br:10])(=[O:19])=[O:18])[CH2:8][CH2:7]1)=[O:5]
Reactant: COC(=O)C1(N)CC1
Reactant: O=S(=O)(Cl)c1ccccc1Br
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(NS(=O)(=O)c2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.9 %

Procedure:
methyl-1-aminocyclopropanecarboxylate hydrochloride (300 mg, 1.979 mmol) was dissolved in CH2Cl2 (7 ml), added with 2-bromobenzene-1-sulfonyl chloride (550 mg, 2.17 mmol) and triethylamine (1.1 ml, 7.92 mmol), and stirred at room temperature for 12 hours. The resultant solution was added with H2O, extracted with CH2Cl2 (×2), dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed. The resultant mixture was purified with column chromatography so as to obtain methyl-1-(2-bromophenylsulfonamido)cyclopropanecarboxylate (560 mg, 1.68 mmol, 85%).
Reaction SMILES: [CH2:1]([N:4]([C@H:17]([CH3:30])[CH2:18][N:19]([CH2:27][CH:28]=[CH2:29])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6])C=C>ClCCl>[C:23]([O:22][C:20]([N:19]1[CH2:27][CH:28]=[CH:29][CH2:1][N:4]([S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])(=[O:6])=[O:7])[C@H:17]([CH3:30])[CH2:18]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: C=CCN(C[C@@H](C)N(CC=C)S(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: C[C@@H]1CN(C(=O)OC(C)(C)C)C/C=C\CN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CC=CCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
550 mg of the compound obtained in Step 3 and 21 mg of Ru catalyst were dissolved in 30 mL of dichloromethane and heated to reflux with stirring in an argon atmosphere. After 16 hours, the reaction solution was cooled to room temperature and concentrated, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 500 mg of the compound of interest as a colorless crystal (97%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3[CH2:22][CH2:23][OH:24])=[CH:15][CH:14]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:28][C:29](=O)[NH:30][C:31]1[N:32]([C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)[N:33]=[C:34]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:35]=1>>[C:36]([C:34]1[CH:35]=[C:31]([NH:30][C:29]([NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C@H:5]([O:12][C:13]3[CH:21]=[C:20]4[C:16]([CH:17]=[N:18][N:19]4[CH2:22][CH2:23][OH:24])=[CH:15][CH:14]=3)[CH2:4][CH2:3]2)=[O:28])[N:32]([C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)[N:33]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: N[C@H]1CC[C@@H](Oc2ccc3cnn(CCO)c3c2)c2ccccc21
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4cnn(CCO)c4c3)c3ccccc32)cc1

Procedure:
The title compound was prepared starting from Intermediate 11b and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 315 mg, 0.78 mmol) by using an analogous procedure to that described in Example 1 step d. LCMS (Method 5): Rt 4.99 min, m/z 578 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.22 (9H, s), 1.81-1.92 (2H, m), 2.02-2.06 (2H, m), 2.31 (3H, s), 3.74-3.75 (2H, m), 4.34 (2H, t, J 5.75), 4.78 (2H, m), 5.53 (1H, t, J 4.8), 6.28 (1H, s), 6.74 (1H, dd, J 8.75 and 2.03), 7.08 (1H, d, J 8.53), 7.27-7.28 (9H, m), 7.57 (1H, d, J 8.75), 7.89 (1H, s), 7.96 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:6][CH:5]=[CH:4][C:3]=1[S:14]([NH:17][C@@H:18]([CH2:22][NH:23][C:24]([C:26]1[S:27][C:28]([Cl:31])=[CH:29][CH:30]=1)=[O:25])[C:19]([OH:21])=O)(=[O:16])=[O:15].[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[C:7]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:6][CH:5]=[CH:4][C:3]=1[S:14]([NH:17][C@H:18]([C:19](=[O:21])[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH2:22][NH:23][C:24]([C:26]1[S:27][C:28]([Cl:31])=[CH:29][CH:30]=1)=[O:25])(=[O:16])=[O:15]
Reactant: O=C(NC[C@H](NS(=O)(=O)c1cccc(N2CCCC2=O)c1Cl)C(=O)O)c1ccc(Cl)s1
Reactant: C1CNCCN1
Product: O=C(NC[C@H](NS(=O)(=O)c1cccc(N2CCCC2=O)c1Cl)C(=O)N1CCNCC1)c1ccc(Cl)s1

Procedure:
Intermediate 47 (150 mg, 0.3 mmol) and piperazine (25.5 mg, 0.3 mmol) were coupled in close analogy to the procedure described in 3.5). The mixture was purified by prep.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[CH:9]=[CH:8][S:7][C:6]=12.[N:10]1[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=1>>[N:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:17])[C:2]2[N:3]=[CH:4][N:5]3[CH:9]=[CH:8][S:7][C:6]=23)=[CH:12][CH:11]=1
Reactant: O=Cc1ccncc1
Reactant: Ic1ncn2ccsc12
Product: OC(c1ccncc1)c1ncn2ccsc12

Procedure:
7-[(Pyridin-4-yl)hydroxymethyl]imidazo[5,1-b]-thiazole (1.32 g) was prepared in the same manner as in step a) of Synthesis Example 1, except that 2.50 g of 7-iodoimidazo[5,1-b]thiazole and 1.05 ml of pyridine-4-aldehyde were used as the starting compounds.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C:27]1[C:28]([CH3:54])=[C:29]2[C:34](=[C:35]([CH3:38])[C:36]=1[CH3:37])[O:33][C@@:32]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][N:49]1[CH:53]=[CH:52][N:51]=[N:50]1)([CH3:39])[CH2:31][CH2:30]2)(C(C)(C)C)(C)C>C1COCC1>[N:49]1([CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][C@:32]2([CH3:39])[CH2:31][CH2:30][C:29]3[C:34](=[C:35]([CH3:38])[C:36]([CH3:37])=[C:27]([OH:26])[C:28]=3[CH3:54])[O:33]2)[CH:53]=[CH:52][N:51]=[N:50]1
Reactant: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)CC[C@@](C)(CCCCCCCCCn1ccnn1)O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCCCCCCCCn1ccnn1)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tetrabutylammonium fluoride (TBAF) (1M in THF, 250 μL) was added dropwise via syringe to a stirred solution of (R)-1-(9-(6-(tert-butyldimethylsilyloxy)-2,5,7,8-tetramethylchroman-2-yl)nonyl)-1H-1,2,3-triazole (65 mg, 0.126 mmol) in dry THF (5 ml). The mixture was stirred at room temperature for 30 minutes until starting material was not detected by TLC. The reaction was then quenched with 500 μL of 1N HCl and diluted with 25 ml of ether, to which an additional 10 ml of dH2O was added. The water phase was extracted again with ether (2×25 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was chromatographed on silica gel (Et2O) to give the pure product (TLC Rf=0.49, EtOAc) as an off-white/yellow solid. (35 mg, 70%)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1>FC(F)(F)C(O)=O>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1cnc(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)cn1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(N2CCC(C3CCNCC3)CC2)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The tert-butyl 1′-(5-methylpyrazin-2-yl)-4,4′-bipiperidine-1-carboxylate (1 g, 2.8 mmol) was dissolved in trifluoroacetic acid and stirred at r.t. for 5 minutes. The solution was concentrated in vac. The residue was dissolved in toluene (10 mL) and concentrated in vac.(×2) to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.O[C:26]1[C:35]([OH:36])=[CH:34][C:33]([C:37]([F:40])([F:39])[F:38])=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]>>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=3)[O:36][C:35]3[CH:34]=[C:33]([C:37]([F:38])([F:40])[F:39])[CH:32]=[C:27]([C:28]([O:30][CH3:31])=[O:29])[C:26]=3[O:8]2)=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(O)c1O
Agent: O=C(Cl)C(=O)Cl
Product: COC(=O)c1cc(C(F)(F)F)cc2c1OC(c1ccc(OC)cc1)(c1ccc(OC)cc1)O2

Procedure:
4,4′-Dimethoxybenzophenone (213 mg, 0.88 mmol, 1.5 eq.), oxalyl chloride (900 mg, 7.1 mmol, 8 eq.) and methyl 2,3-dihydroxy-5-trifluoromethyl-benzoate (130 mg, 0.59 mmol, 1 eq.) were reacted according to GP2.2. The crude product was purified using flash chromato-graphy (silica gel, hexane/Et2O 10:1) to yield the title compound as a yellowish, very viscous oil.
Reaction SMILES: CC[O-].[Na+].[CH2:5]([C:12]1[CH:13]=[C:14]([N:23]([C:35](=[O:42])[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:15]([C:18]([O:20]CC)=O)=[N:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>CCO>[CH2:5]([C:12]1[CH:13]=[C:14]2[C:15]([C:18]([OH:20])=[C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:35](=[O:42])[N:23]2[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][CH:30]=2)=[N:16][CH:17]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CC(=O)N(Cc1ccc(S(C)(=O)=O)cc1)c1cc(Cc2ccccc2)cnc1C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1M NaOEt in EtOH (2.5 mL, 2.5 mmol) was added dropwise to a solution of ethyl 5-benzyl-3-{(3-ethoxy-3-oxopropanoyl)[4-(methylsulfonyl)benzyl]-amino}-pyridine-2-carboxylate (690 mg, 1.26 mmol) in EtOH (6 mL). The mixture was stirred at rt for 30 min, neutralized with 1M HCl (2.5 mL) and the resulting precipitate was collected by filtration washing with 1:1 water/EtOH. This procedure afforded the product as an off-white solid: 1H NMR (CDCl3) δ 14.07 (1H, br s), 8.56 (1H, s), 7.79 (2H, d, J=8 Hz), 7.30 (3H, m), 7.19 (2H, d, J=8 Hz), 7.02 (3H, m), 5.40 (2H, br s), 4.53 (2H, q, J=7 Hz), 4.04 (2H, s), 3.01 (3H, s), 1.48 (3H, s); HRMS calcd for C26H24N2O6S+H+: 493.1433. Found: 493.1422.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[S-:11][C:12]#[N:13].[K+]>C(O)C>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][S:11][C:12]#[N:13]
Reactant: N#C[S-]
Reactant: O=C(CBr)c1ccccc1
Agent: [K+]
Solvent: CCO
Product: N#CSCC(=O)c1ccccc1
Temperature: 25 °C
Yield: 67.6 %

Procedure:
A solution of α-bromoacetophenone (10.0 g, 50.0 mmol) and potassium thiocyanate (4.90 g, 50.0 mmol) in ethanol (80 ml) was stirred at 80° C. for 3 hours. After cooling to room temperature, a precipitated solid was collected by filtration, washed with 50% ethanol in water and dried to give 5.99 g (67.6%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]([OH:13])=O)[NH:10][C:4]=2[CH:3]=1.Cl.[NH2:15][C@@H:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]([N:19]([CH3:21])[CH3:20])=[O:18].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:21][N:19]([CH3:20])[C:17]([CH:16]([NH:15][C:11]([C:9]1[NH:10][C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][C:5]=2[CH:8]=1)=[O:13])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:18]
Reactant: O=C(O)c1cc2cnc(Cl)cc2[nH]1
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(Cc1ccccc1)NC(=O)c1cc2cnc(Cl)cc2[nH]1
Reaction time: 0.08 h

Procedure:
To a solution of 6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (Preparation 116, 47 mg, 0.24 mmol) in DMF (5 mL, anhydrous) was added 2-(S)-amino-N,N-dimethyl-3-phenylpropionamide hydrochloride (Preparation 8, 56 mg, 0.25 mmol), DIPEA (131 μL, 0.75 mmol) and HOBt (40 mg, 0.26 mmol) sequentially. The solution was stirred for 5 min prior to the addition of EDCI (55 mg, 0.29 mmol) in one portion. The resulting solution was stirred for 12 h at rt. The reaction mixture was partitioned between ethyl acetate (50 mL) and water/brine (150 mL, 1:1). The layers were separated and the aqueous phase extracted with ethyl acetate (3×50 mL), then the combined organics were washed with dilute HCl solution (1M, 50 mL), dilute NaOH solution (1M, 50 mL) and brine (50 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo. Purification via flash column chromatography eluting with toluene/acetone (3:1) gave the title compound. δH (CDCl3): 2.88, 3.05 (6H, 2s), 3.18, 3.28 (2H, 2 dd), 5.41 (2H, m), 7.02 (1H, s), 7.28-7.34 (6H, m), 8.17 (1H, d), 8.68 (1H, s), 10.58 (1H, br s); m/z (ES+)=371.13 [M+H]+; RT=3.28 min.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]#[C:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:22][O:23][C:24](=[O:30])[C:25]([CH3:29])([CH3:28])[CH2:26][CH3:27])=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[CH3:28][C:25]([CH3:29])([CH2:26][CH3:27])[C:24](=[O:30])[O:23][CH2:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=1[C:14]#[C:13][CH2:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4](=[O:31])[C:3]([OH:32])=[O:2])=[CH:10][CH:9]=1
Reactant: CCC(C)(C)C(=O)OCc1cccc(C)c1C#CCOc1ccc(C(=O)C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(C)(C)C(=O)OCc1cccc(C)c1C#CCOc1ccc(C(=O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.4 %

Procedure:
A solution of 4-[3-[2-[(2,2-dimethyl-1-oxobutoxy)methyl]-6-methylphenyl]-2-propynyloxy]-alpha-oxobenzeneacetic acid methyl ester (1.25 g) in methanol (5 mL) was treated with 3N sodium hydroxide solution (1.25 mL) and the mixture was stirred for 5 minutes at room temperature. Most of the methanol was removed under reduced pressure, and the concentrate was partitioned between diethyl ether (25 mL,) and water (25 mL). The separated aqueous layer was acidified with 1N hydrochloric acid (5 mL) and extracted with diethyl ether (2×50 mL). The combined organic phases were washed with brine, dried (Na2SO4) and evaporated in vacuo to give 1.13 g of 4-[3-[2-[(2,2-dimethyl-1-oxobutoxy)methyl]-6-methylphenyl]-2-propynyloxy]-alphaoxobenzeneacetic acid as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)[CH2:11][CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[N:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)[CH2:11][CH3:12]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCCc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCc1ccc(C=Nc2ccc(C#N)cc2)cc1

Procedure:
A mixture of 5.9 g. of p-aminobenzonitrile and 7.4 g. of p-n-propylbenzaldehyde in 100 ml. of benzene is treated with 150 mg. of p-toluenesulfonic acid and reacted as described in Example 1. After evaporation, there remian 12.5 g. of a yellowish oil which crystallizes with cooling. Purification is carried out by several recrystallizations from isopropanol as described in Example 1. The p-[(p-n-propylbenzyliden)amino]benzonitrile which is obtained has a melting point of 64.8°-65.5°C. and a clearing point of 77.6°C. UV (ethanol): ε280 = 24300 (shoulder at 310 nm). The nuclear magnetic resonance, mass spectrum, infrared and microanalysis data confirm the structure.