Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1C)([CH3:3])[CH3:2].[C:12]([OH:19])(=[O:18])/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16].[C:20]([OH:51])(=[O:50])[CH2:21][CH2:22][C@H:23]([NH:27][C:28]([C:30]1[CH:49]=[CH:48][C:33]([NH:34][CH2:35][C:36]2[N:47]=[C:46]3[C:39]([N:40]=[C:41]([NH:43][C:44]3=[O:45])[NH2:42])=[N:38][CH:37]=2)=[CH:32][CH:31]=1)=[O:29])[C:24]([OH:26])=[O:25]>>[NH2:42][CH:41]1[NH:43][C:44]([OH:45])=[C:46]2[C:39]([N:38]=[CH:37][C:36]([CH2:35][NH:34][C:33]3[CH:32]=[CH:31][C:30]([C:28]([NH:27][CH:23]([C:24]([OH:26])=[O:25])[CH2:22][CH2:21][C:20]([O:51][C:9]4[C:4]([CH:1]([CH3:2])[CH3:3])=[C:5]([C:6]([OH:10])=[CH:7][CH:8]=4)[O:16][C:15](=[O:17])/[CH:14]=[CH:13]/[C:12]([OH:19])=[O:18])=[O:50])=[O:29])=[CH:49][CH:48]=3)=[N:47]2)=[N:40]1
Reactant: O=C(O)/C=C/C(=O)O
Reactant: Cc1c(O)cccc1C(C)C
Reactant: Nc1nc2ncc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)nc2c(=O)[nH]1
Product: CC(C)c1c(OC(=O)CCC(NC(=O)c2ccc(NCc3cnc4c(n3)=C(O)NC(N)N=4)cc2)C(=O)O)ccc(O)c1OC(=O)/C=C/C(=O)O

Procedure:
A second antimicrobial compound was formed by combining the isopropyl-o-cresol from Example 2 with fumaric acid and folic acid. (E)-4-[3-({4-[(4-{[(2-amino-4-hydroxy-2,3-dihydro-6-pteridinyl)methyl]amino}benzoyl)amino]-4-carboxybutanoyl}oxy)-6-hydroxy-2-isopropylphenoxy]-4-oxo-2-butenoic acid (fumo-cresol-folin or FCF), was formed by combining 50 grams isopropyl-o-cresol was combined with 25 ml fumaric acid (90% purity), and 25 ml folic acid (95% purity). The mixture was heated to a temperature of 80° C. and mixed in a high speed turbo mixer for 3 minutes at a speed of 1,000 revolutions per minute.
Reaction SMILES: C([C:5]1([CH2:12][CH2:13][O:14][CH3:15])[C:10](=[O:11])[CH2:9][CH2:8][S:7][CH2:6]1)(OC)=O.[I-].[Li+].O.Cl>CN(C=O)C>[CH3:15][O:14][CH2:13][CH2:12][CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][S:7][CH2:6]1
Reactant: COCCC1(C(=O)OC)CSCCC1=O
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCC1CSCCC1=O
Yield: 50.1 %

Procedure:
To a solution of 2.4 g (10.3 mmol) of product from Step A in 50 ml DMF was added 6 g (44.8 mmol) lithium iodide. The resulting solution was refluxed under N2 for 2 hours. The reaction mixture was poured into 500 ml H2O/HCl and extracted with ethyl acetate. THe organic solution was washed with water; saturated NaCl, dried over MgSO4 and concentrated in vacuo to give 1.7 g crude product which was chromatographed through a pressure column eluting with 10% ethyl acetate/n-hexane to give 0.9 g of title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:50][C:51]1[CH:59]=[CH:58][CH:57]=[CH:56][C:52]=1[CH:53]([OH:55])[CH3:54]>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:39](=[O:41])[O:55][CH:53]([C:52]1[CH:56]=[CH:57][CH:58]=[CH:59][C:51]=1[Cl:50])[CH3:54]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)c1ccccc1Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC(C)c4ccccc4Cl)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Yield: 81.4 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (61 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (91 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 15 min. Subsequently, 2-chloro-α-methylbenzyl alcohol (57 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (77 mg, yield 69%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[P:7](Cl)([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[S:8].[C:16]([C:18]1[S:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:21][C:22]=1[OH:23])#[N:17]>C(#N)C>[C:16]([C:18]1[S:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:21][C:22]=1[O:23][P:7]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[S:8])#[N:17]
Reactant: CCOP(=S)(Cl)OCC
Reactant: CCCCOc1cc(O)c(C#N)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOc1cc(OP(=S)(OCC)OCC)c(C#N)s1
Temperature: 20 °C
Reaction time: 24 h
Yield: 80.6 %

Procedure:
7 g of potassium carbonate and 9.4 g of O,O-diethyl chlorothiophosphate were added to a solution of 9.8 g of 2-cyano-3-hydroxy-5-n-butoxy-thiophene in 150 ml of acetonitrile and the mixture was stirred for 24 hours at 20° C. and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with benzene yielded 14 g of 2-cyano-3-(diethoxythiophosphoryloxy)-5-n-butoxy-thiophene with a refractive index of nD20 =1.525.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[CH:43][C:6]([CH2:7][N:8]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:32][CH3:33])=[C:29]([F:31])[CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=[O:22])[N:10]=2)=[CH:5][CH:4]=1.[CH3:45][Mg]Br.[Cl-].[NH4+].O>C1COCC1.CCOC(C)=O>[CH3:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:44][CH:43]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:23]=[C:20]([CH:21]([OH:22])[CH3:45])[CH:19]=[N:18][C:17]=3[NH:24][C:25]3[CH:26]=[N:27][C:28]([O:32][CH3:33])=[C:29]([F:31])[CH:30]=3)[N:10]=2)=[CH:40][CH:39]=1
Reactant: C[Mg]Br
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 82.6 %

Procedure:
5-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde (1.0538 g, 1.769 mmol) was suspended in THF (16 mL) and the reaction flask was cooled in an ice water bath. Then, methylmagnesium bromide (3.0 M in diethyl ether, 1.80 mL, 5.40 mmol) was added via syringe, and the reaction was stirred at 0° C. for 25 min. Then, the reaction was treated with saturated ammonium chloride (3 mL, dropwise at first as gas evolution is observed) and water (20 mL). The reaction was diluted with EtOAc and the layers were separated. The aqueous phase was extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted filter with about 2 inches of silica gel; 100:1 DCM/MeOH (to elute non-polar impurities) to 40:1 (to elute product)) to give 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanol (893.8 mg). 1H NMR (400 MHz, CDCl3) δ 11.86 (s, 1H), 8.83 (d, J=2.35 Hz, 1H), 8.32 (d, J=2.35 Hz, 1H), 8.01 (dd, J=12.13 Hz, 2.15 Hz, 1H), 7.96 (d, J=2.35 Hz, 1H), 7.21 (dd, J=10.76 Hz, 8.61 Hz, 4H), 6.87 (dd, J=12.13 Hz, 8.80 Hz, 4H), 4.94-4.81 (m, 5H), 4.02 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 2.59 (s, 3H), 1.73 (d, J=3.72 Hz, 1H), 1.53 (d, J=6.46 Hz, 3H). m/z (ESI, pos. ion) 612 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([Br:12])=[CH:6][C:3]=1[CH:4]=O.[NH2:13][C:14](N)=[O:15]>>[Br:12][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][C:8]=1[O:10][CH3:11])[N:1]=[C:14]([OH:15])[N:13]=[CH:4]2
Reactant: COc1cc(N)c(C=O)cc1Br
Reactant: NC(N)=O
Product: COc1cc2nc(O)ncc2cc1Br
Temperature: 180 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
A mixture of 2-amino-5-bromo-4-methoxybenzaldehyde (3 g, 13.1 mmol) and urea (12 g, 196.5 mmol) was stirred at 180° C. for 2 h. LCMS showed the reaction was completed. The reaction mixture was cooled to RT and washed with water (3×100 mL). The precipitate was collected and dried to give the title compound (3 g, crude) as a yellow solid. MS (ES+) C8H7BrN2O2 requires: 254, 256. found: 255, 257 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C@@H:12]([NH:30]C(=O)OC(C)(C)C)[C:13](=[O:29])[NH:14][C:15]1[CH:16]=[C:17]2[C:27](=[O:28])[NH:26][N:25]=[CH:24][C:19]3=[CH:20][NH:21][C:22]([CH:23]=1)=[C:18]23.[ClH:38]>O1CCOCC1>[ClH:38].[NH2:30][C@H:12]([CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:13]([NH:14][C:15]1[CH:16]=[C:17]2[C:27](=[O:28])[NH:26][N:25]=[CH:24][C:19]3=[CH:20][NH:21][C:22]([CH:23]=1)=[C:18]23)=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)Nc1cc2c3c(c[nH]c3c1)C=NNC2=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](Cc1ccc2ccccc2c1)C(=O)Nc1cc2c3c(c[nH]c3c1)C=NNC2=O
Yield: 97 %

Procedure:
Preparation of example 179 from the title compound of Example 158 (57 mg, 0.115 mmol) and 4M HCl in dioxane (10 mL) was carried out analogously to Example 91. Isolation, also in an analogous manner afforded the title compound (48 mg, 0.111 mmol) as an orange/yellow powder in 97% yield.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#N)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=O)C.[CH2:17](Br)[CH2:18][CH2:19]C.[OH-].[K+].C(O)CCC>O.C(Cl)(Cl)Cl>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:17][CH2:18][CH3:19])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Reactant: CCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCCCO
Solvent: O
Product: CCCCSc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
5 G. of 1-acetamido-2-nitro-4-thiocyanatobenzene and 2.8 ml. of n-butyl bromide are added to a solution of 4.8 g. of potassium hydroxide in 70 ml. of n-butanol. The mixture is left overnight at room temperature, then diluted with water. 1-Amino-2-nitro-4-n-butylthiobenzene is isolated by extraction with chloroform.
Reaction SMILES: [N:1]1[CH:6]=[CH:5]N=[CH:3][C:2]=1[C:7]1[N:11]2[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:10]2=[N:9][N:8]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:20]=1[CH3:29].Br[CH2:31]C1C=CC=C(Cl)C=1Cl>>[CH3:29][C:20]1[C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:14]1[CH2:13][CH2:12][N:11]2[C:7]([C:2]3[CH:3]=[CH:31][CH:5]=[CH:6][N:1]=3)=[N:8][N:9]=[C:10]2[C:15]1=[O:16]
Reactant: Clc1cccc(CBr)c1Cl
Reactant: O=C1NCCn2c1nnc2-c1cnccn1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Product: Cc1c(CN2CCn3c(nnc3-c3ccccn3)C2=O)cccc1C(F)(F)F
Yield: 75 %

Procedure:
Example 10 was made in a manner analogous to Example 2 substituting Intermediate 2 for Intermediate 1 and 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene for 1-(bromomethyl)-2,3-dichlorobenzene to provide the desired compound as a white solid (53 mg, 75%). MS (ESI): mass calcd. for C19H16F3N5O, 387.1; m/z found, 388.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.78-8.66 (m, 1H), 8.29 (d, J=7.9 Hz, 1H), 8.05 (dt, J=7.8, 1.7 Hz, 1H), 7.63 (dd, J=16.8, 7.8 Hz, 2H), 7.57 (ddd, J=7.6, 4.9, 1.1 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 4.87 (dd, J=15.9, 9.8 Hz, 4H), 3.85-3.74 (m, 2H), 2.41 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11](=[O:35])[C@H:12]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[C@@H:13]([C:23](=[O:26])[NH:24][OH:25])[CH2:14][O:15]CC1C=CC=CC=1)=[O:4]>CO.[Pd]>[CH3:1][NH:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11](=[O:35])[C@H:12]([C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)[C@@H:13]([C:23](=[O:26])[NH:24][OH:25])[CH2:14][OH:15])=[O:4]
Reactant: CNC(=O)[C@@H]1CCCCN1C(=O)[C@H](c1ccc(OC)cc1)[C@H](COCc1ccccc1)C(=O)NO
Agent: [Pd]
Solvent: CO
Product: CNC(=O)[C@@H]1CCCCN1C(=O)[C@H](c1ccc(OC)cc1)[C@H](CO)C(=O)NO

Procedure:
A solution of hydroxamic acid 7 (100 mg, 0.21 mmol) in 20 ml of methanol was hydrogenated under normal pressure with 50 mg of palladium on barium sulfate for about 5 hours. After filtration of the catalyst the solvent was evaporated and the crude product was purified by preparative HPLC to give a white solid. Yield: 53 mg (65%).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH:25][CH3:26])[O:22][N:21]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH:25][CH3:26])[O:22][N:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CNc1nc(-c2ccc3c(c2)c(-c2cncc(OC(C)C)n2)cn3S(=O)(=O)c2ccc(C)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CNc1nc(-c2ccc3[nH]cc(-c4cncc(OC(C)C)n4)c3c2)no1
Temperature: 100 °C
Yield: 20.5 %

Procedure:
To a solution of 3-(3-(6-isopropoxypyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-methyl-1,2,4-oxadiazol-5-amine (160 mg, 0.32 mmol) in 1,4-dioxane (1.6 mL) was added 10% aq NaOH (0.8 mL) and the reaction was heated at 100° C. for 2 h. The mixture was cooled to RT and treated with ice cold water (1.5 mL). The precipitate was collected through filtration and the crude product was purified with preparative HPLC (eluent: 20-70% AcCN in H2O with 0.01% TFA) to give 3-(3-(6-isopropoxypyrazin-2-yl)-1H-indol-5-yl)-N-methyl-1,2,4-oxadiazol-5-amine (23 mg, 20.7%). MS (ESI, pos. ion) m/z: 351.1 (M+1); 1H NMR (400 MHz, DMSO-d6): δ 11.96 (s, 1H), 9.15 (s, 1H), 8.74 (s, 1H), 8.38 (d, J=1.6 Hz, 1H), 8.18 (dd, J=8.8, 4.4 Hz, 1H), 7.94 (s, 1H), 7.77 (dd, J=8.4, 1.2 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 5.56-5.53 (m, 1H), 2.96 (d, J=4.0 Hz, 3H), 1.49 (d, J=6.0 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][Si:4]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])[CH2:5][CH2:6][C:7](N)=[S:8])[CH3:2].[H][H]>[Co](=S)(=S)=S>[SH:8][CH2:7][CH2:6][CH2:5][Si:4]([O:13][CH2:14][CH3:15])([O:3][CH2:1][CH3:2])[O:10][CH2:11][CH3:12]
Reactant: [H][H]
Reactant: CCO[Si](CCC(N)=S)(OCC)OCC
Agent: S=[Co](=S)=S
Product: CCO[Si](CCCS)(OCC)OCC
Temperature: 195 °C

Procedure:
Into a clean, dry 300 cubic centimeter high pressure reactor were added 150 grams (0.60 moles) of beta-triethoxysilylthiopropionamide product (Example II pilot plant lot containing 5% beta-cyanoethyltriethoxysilane starting material) and 2.5 weight percent of cobalt trisulfide. The reactor was sealed, initially pressurized to 600 psig with hydrogen and placed in a rocker. The vessel was heated to 195° C. internal temperature which raised the hydrogen pressure to 1100 psig. Heating was maintained for 8 hours with agitation. Hydrogen was continuously fed into the reactor to maintain the hydrogen pressure at about 1000 psig. The pressure never exceeded 1100 psig. The pressure at the end of the reaction was 575 psig. The reaction produced the desired gamma-mercaptopropyltriethoxysilane.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].[OH:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[CH:22][N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[CH:22][N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1O
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1F

Procedure:
In a similar manner as described for example B11, 172 mg of 1-(bromomethyl)-2-fluorobenzene, 200 mg of methyl 3-hydroxy-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate, 121 mg of potassium carbonate in 5 ml anhydrous DMF yield the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2.[CH:40]1([S:43](Cl)(=[O:45])=[O:44])[CH2:42][CH2:41]1>>[CH:27]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2)[C:12]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[C:4]1[CH2:3][CH2:2][NH:1][S:43]([CH:40]1[CH2:42][CH2:41]1)(=[O:45])=[O:44])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccc(OCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)C1CC1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)C3CC3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 75 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 5, Example 1)was added cyclopropanesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 75% yield.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@@H:4]([NH:12][CH3:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:14]([O:16][C:17]([CH:19]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[N:20]1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29](C=O)[CH:28]=1)=[O:18])[CH3:15].[C:35]([BH3-])#N.[Na+].C(O)(=O)C>CO.C(OCC)(=O)C>[CH2:14]([O:16][C:17]([CH:19]1[CH2:23][CH2:22][S:21](=[O:24])(=[O:25])[N:20]1[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([CH2:13][NH:12][C@H:4]([CH2:3][N:2]([CH3:35])[CH3:1])[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:32]=1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1CCS(=O)(=O)N1Cc1cccc(C=O)c1
Reactant: CNC[C@H](Cc1ccccc1)NC
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C1CCS(=O)(=O)N1Cc1cccc(CN[C@@H](Cc2ccccc2)CN(C)C)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 112.9 %

Procedure:
To a solution of (S)—N,N′-dimethyl-3-phenyl-propane-1,2-diamine (120 mg, 0.673 mmol) in methanol (2 mL) under argon was added a solution of 2-(3-formyl-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester (Intermediate 4; 230.5 mg, 0.740 mmol) in methanol (4 mL). The solution was cooled 0° C. in an ice bath and to this was added sodium cyanoborohydride (63.4 mg, 1.01 mmol) and acetic acid (0.3 mL). The solution was allowed to warm to room temperature and stirred for 16 h under argon. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (2×10 mL) and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to give crude 2-{3-[((S)-1-dimethylaminomethyl-2-phenyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester (360 mg) as colorless oil.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]1([C:31]([Cl:33])=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[ClH:33].[C:21]1([C:31]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: NCCCSc1ccncc1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)c1cccc2ccccc12
Yield: 67.1 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.78 ml (19.9 mmol) of trietylamine in 40 ml of methylene chloride was added 0.75 ml (4.98 mmol) of 1-naphthoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain the powder which was washed with ether and dried to obtain 1.00 g of the desired compound (free base) (74.8%, yellow powder), mp: 113.0°-114.0° C.
Reaction SMILES: [CH2:1]([C:4]1[O:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8](=O)[CH:9]=1)[CH2:2][CH3:3].O>C(O)C.Cl.[Pd]>[CH2:1]([CH:4]1[CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5]1)[CH2:2][CH3:3]
Reactant: CCCc1cc(=O)c2ccccc2o1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCC1CCc2ccccc2O1

Procedure:
A solution of 44 g (234 mmol) of 2-propyl-1-benzopyran-4-one in 350 ml of ethanol and 125 ml of concentrated hydrochloric acid is hydrogenated for 8 hours under a pressure of 500 kPa, in the presence of 14 g of 10% palladium on carbon containing 50% of water. The mixture is then filtered and the filtrate is concentrated under reduced pressure. By chromatography of the residue on a silica column using dichloromethane, 26 g of product are obtained in oil form.
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].CS(O[CH2:19][CH:20]=[CH:21][CH3:22])(=O)=O>>[CH2:19]([N:5]1[C:6]([CH3:9])=[C:7]([CH3:8])[C:3]([CH:1]=[O:2])=[C:4]1[C:10]([O:12][CH3:13])=[O:11])[CH:20]=[CH:21][CH3:22]
Reactant: CC=CCOS(C)(=O)=O
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Product: CC=CCn1c(C)c(C)c(C=O)c1C(=O)OC

Procedure:
The title compound (cis/trans=93/7) was prepared as a pale brown oil in 33.4% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 2-butenyl methanesulfonate (cis/trans=96/4).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[C:16]([N:23]1[CH2:29][CH2:28][CH2:27][C@H:24]1[CH2:25]O)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:19]([O:18][C:16]([N:23]1[CH2:29][CH2:28][CH2:27][C@H:24]1[CH2:25][O:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1ccc(O)cc1C(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1C(=O)OC
Yield: 102.5 %

Procedure:
To a stirred solution of dimethyl 4-hydroxyphthalate (3.00 g, 14.27 mmol), N-Boc-prolinol (2.87 g, 14.26 mmol), Ph3P (4.49 g, 17.12 mmol) in THF (50 mL) was added DIAD (3.40 mL, 17.27 mmol) at 0° C. Then the resulting mixture was heated under reflux overnight. The resulting mixture was evaporated and the residue was purified by column chromatography on silica-gel with n-hexane-EtOAc (3:1, v/v) as eluent to give 5.75 g (q.y.) dimethyl (S)-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl methoxy]phthalate as an oil. 1H-NMR (CDCl3) δ1.47 (s, 9 H), 1.86-2.05 (m, 4 H), 3.36-3.40 (m, 2 H), 3.87 (m, 3 H), 3.91 (s, 3 H), 3.96-4.19 (m, 3 H), 7.03-7.24 (m, 2 H), 7.80 (m, 1H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[N:13]=[C:14]([CH:17](O)[C:18]2[NH:19][C:20]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[C:21]3[C:26](=[O:27])[N:25]([CH3:28])[C:24](=[O:29])[N:23]([CH3:30])[C:22]=23)[S:15][CH:16]=1.[C:39]([O:46][CH3:47])(=[O:45])[CH2:40][C:41]([O:43][CH3:44])=[O:42]>C1COCC1>[Cl:11][C:12]1[N:13]=[C:14]([CH:17]([C:18]2[NH:19][C:20]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[C:21]3[C:26](=[O:27])[N:25]([CH3:28])[C:24](=[O:29])[N:23]([CH3:30])[C:22]=23)[CH:40]([C:39]([O:46][CH3:47])=[O:45])[C:41]([O:43][CH3:44])=[O:42])[S:15][CH:16]=1
Reactant: COC(=O)CC(=O)OC
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C(O)c3nc(Cl)cs3)c2n(C)c1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)C(c1nc(Cl)cs1)c1[nH]c(-c2cccc(F)c2)c2c(=O)n(C)c(=O)n(C)c12

Procedure:
NaHMDS solution (1M in THF, 7.13 mL, 7.13 mmol) was added slowly to a mixture of 7-((4-chlorothiazol-2-yl) (hydroxy)methyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (Example 27, step 1) (1 g, 2.376 mmol), dimethyl malonate (0.819 mL, 7.13 mmol) and boron trifluoride THF complex (0.236 mL, 2.139 mmol) in THF (30 mL).