Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)(=[O:4])=[O:3].[CH:15]1[C:23]2[N:18]([CH:19]=[CH:20][C:21](=O)[CH:22]=2)[CH2:17][CH:16]=1>>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:21]2[CH2:22][CH:23]3[N:18]([CH2:17][CH2:16][CH2:15]3)[CH2:19][CH:20]=2)=[CH:6]1)(=[O:4])=[O:3]
Reactant: O=c1ccn2c(c1)C=CC2
Reactant: CS(=O)(=O)n1ccc2cc(N)ccc21
Product: CS(=O)(=O)n1cc(C2=CCN3CCCC3C2)c2cc(N)ccc21

Procedure:
The N-(methanesulfonyl)-5-amino-1H-indole (1.06 g, 5.00 mmol) and the 7-indolizinone (900 mg, 6.50 mmol) were converted to product by the procedure of Example 2 to give 807 mg. (48.7%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[Cl:25][C:26]1[C:32]([O:33][CH3:34])=[CH:31][C:29]([NH2:30])=[C:28]([CH3:35])[CH:27]=1.C(=O)(O)[O-].[Na+]>C(OCCO)C.O>[Cl:15][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:30][C:29]3[CH:31]=[C:32]([O:33][CH3:34])[C:26]([Cl:25])=[CH:27][C:28]=3[CH3:35])=[C:3]([C:16]#[N:17])[CH:4]=[N:5]2)=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13]
Reactant: COc1cc(N)c(C)cc1Cl
Reactant: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCCO
Solvent: O
Product: COc1cc(Nc2c(C#N)cnc3cc(Cl)c([N+](=O)[O-])cc23)c(C)cc1Cl
Temperature: 120 °C
Reaction time: 4 h
Yield: 82.7 %

Procedure:
To a stirred suspension of 0.9 g (3.3 mmol) of 4,7-dichloro-6-nitro-3-quinolinecarbonitrile and pyridine hydrochloride (0.381 g, 3.3 mmol) in 2-ethoxyethanol (10 mL) under nitrogen, is added 0.634 g (3.69 mmol) of 4-chloro-5-methoxy-2-methylaniline (WO 8501939 A1). The reaction is stirred at 120° C. for 4 hours. The mixture is then cooled to room temperature and solid sodium bicarbonate is added until foaming subsided. Water is added to the reaction mixture (40 mL), which is subsequently extracted with 3×30 mL ethyl acetate. After combining the organic portions and drying with sodium sulfate, the solvents are removed in vacuo. The residue obtained is purified by flash chromatography, eluting with 99.5:0.5 methylene chloride/methanol. The solid obtained is recrystallized from hot ethyl acetate to afford 1.1 g of an orange crystalline solid, mp 217–219° C.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH3:11])[CH:7]([O:12][C:13](=[O:15])[CH3:14])[CH:6]1OC(=O)C)=[O:4].C(OC1C(C)CCN(C(O)=O)C1O)(=O)C>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]([N:5]1[CH:6]=[C:7]([O:12][C:13](=[O:15])[CH3:14])[CH:8]([CH3:11])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)N1CCC(C)C(OC(C)=O)C1OC(C)=O
Agent: CC(=O)OC1C(C)CCN(C(=O)O)C1O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)N1C=C(OC(C)=O)C(C)CC1
Temperature: 141 °C
Reaction time: 8 h

Procedure:
101.9 g (0.649 mol) of the mixture of 2,3-diacetoxy-4-methyl-piperidine-1-carboxylic acid methyl ester and 3-acetoxy-2-hydroxy-4-methyl-piperidine-1-carboxylic acid, was concentrated under reduced pressure until a solid formed. The solid was then added to a 2 L round bottom flask equipped with a nitrogen outlet, condenser and thermocouple. To this mixture was added acetic anhydride (430 ml) and then refluxed at 141° C. for two hours. The solution was stirred overnight at room temperature. Most of the acetic anhydride was removed under reduced pressure and the remaining amount was removed by adding H2O (400 ml) and a 5% solution of NaHCO3 until the pH>7. The aqueous mixture was extracted with ethyl acetate (3×250 ml), the organic layers were combined and the ethyl acetate was removed under reduced pressure. Approximately 119.0 g of a thick brown oil material 5-acetoxy-4-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid methyl ester was recovered. The TLC indicates conversion to product 5-acetoxy-4-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid methyl ester as the major component. The material was split evenly into two portions for separate hydrolysis reactions.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])([CH3:15])/[C:11](=[N:13]/[OH:14])/[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:29](OC(=O)C)(=O)[CH3:30]>CN(C=O)C>[CH2:1]([O:8][CH2:9][C:10]([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])([CH3:15])[C:11]1[N:12]=[C:29]([CH3:30])[O:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(COCc1ccccc1)(NS(=O)C(C)(C)C)/C(N)=N/O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C(C)(COCc2ccccc2)NS(=O)C(C)(C)C)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a solution of (Z)-3-(benzyloxy)-2-(1,1-dimethylethylsulfinamido)-N′-hydroxy-2-methylpropanimidamide (Example 112b, 1.25 g, 3.82 mmol) in dry DMF (25 ml) was added potassium carbonate (633 mg, 4.58 mmol) followed by addition of acetic anhydride (390 mg, 360 uL, 3.82 mmol). The reaction mixture was stirred at room temperature for 1 hour and was then stirred at 120° C. for 2 hours. DMF was removed in vacuo and the residue was dissolved in ethyl acetate which was extracted with a 1.0M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (1.20 g, purity: 80%, 72%) as a light yellow oil. MS (ESI, m/z): 352.6 (M+H+).
Reaction SMILES: [C:1]([C:4]1[C:9]2[N:10]=[C:11]([C:13]3[CH:31]=[CH:30][C:16]([CH2:17][N:18](C)[C:19](=O)OCC4C=CC=CC=4)=[CH:15][CH:14]=3)[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2]>C1COCC1.[Pd]>[CH3:19][NH:18][CH2:17][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[O:12][C:8]3[C:9](=[C:4]([C:1]([NH2:2])=[O:3])[CH:5]=[CH:6][CH:7]=3)[N:10]=2)=[CH:31][CH:30]=1
Reactant: CN(Cc1ccc(-c2nc3c(C(N)=O)cccc3o2)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CNCc1ccc(-c2nc3c(C(N)=O)cccc3o2)cc1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
Benzyl 4-(4-carbamoylbenzo[d]oxazol-2-yl)benzyl(methyl)carbamate (0.050 g, 0.12 mmol) was dissolved in THF (10 mL) and 10% Pd/C (5.0 mg) was added, Hydrogen was purged into the mixture, and the mixture was maintained at room temperature for 6 hr, then the Pd/C was filtered off and the filtrate was condensed to get 2-(4-((methylamino)methyl)phenyl)benzo[d]oxazole-4-carboxamide (0.0212 g, 69.6% yield). 1H-NMR (400 MHz, DMSO-d6) δ 2.59 (s, 3H), 4.24-4.26 (t, J=5.0 Hz, 1H), 7.56-7.60 (t, J=8.0 Hz, 1H), 7.80-7.82 (d, J=8.0 Hz, 2H), 8.00-8.07 (m, 3H), 8.38-8.40 (d, J=8.0 Hz, 2H), 8.49 (s, 1H), 9.39 (s, 2H); LC-MS (ESI) m/z 282 [M+1]+.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[Br:13][C:14]1[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=1.[C:22]([O:26][C:27]([N:29]1[C@H:34]([C:35](O)=O)[CH2:33][C@@H:32]2[C@H:30]1[CH2:31]2)=[O:28])([CH3:25])([CH3:24])[CH3:23].ON1C2C=CC=CC=2N=N1>C(Cl)Cl.C(O)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]2[N:20]=[C:35]([C@@H:34]3[CH2:33][C@@H:32]4[C@@H:30]([CH2:31]4)[N:29]3[C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])[NH:21][C:16]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Reactant: Nc1ccc(Br)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc(Br)cc2[nH]1
Temperature: 75 °C
Reaction time: 16 h
Yield: 63.2 %

Procedure:
EDCI.HCl (2.65 g, 13.8 mmol) was added to a mixture of 4-bromobenzene-1,2-diamine 2.35 g, 12.6 mmol), (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (3.00 g, 13.2 mmol) and 1-hydroxybenzotriazole (1.93 g, 12.6 mmol) in CH2Cl2 (80 mL) and stirred at ambient conditions for 16 h. The mixture was then diluted with CH2Cl2, washed with water, dried (brine; MgSO4), filtered and concentrated in vacuo to provide a brown foam. Acetic acid (80 mL) was added to the foam and the mixture was heated at 75° C. (bath temperature) for 5 h. The volatile component was removed in vacuo and the residue was dissolved in EtOAc, washed with saturated NaHCO3 solution and the organic phase was dried (brine; MgSO4), filtered and concentrated in vacuo. The resultant crude material was submitted to flash chromatography (silica gel; 50-100% EtOAc/hexanes) to provide (1R,3S,5R)-tert-butyl 3-(6-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (3.01 g, 7.96 mmol, 63.3% yield) as a light orange foam, which was used without further purification. The reaction also yielded 847 mg of same product with lower purity. An aliquot of the collected material was purified further by preparative HPLC (C-18/30-100% CH3CN-water+0.1% NH4OAc) to achieve an analytical sample. LC-MS retention time 1.248 min; calcd. for C17H21BrN3O2: 378.08. found m/z 380.05 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min and an analysis time of 4 min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 7.67 (br s, 1H), 7.43 (br s, 1H), 7.34 (d, J=8.6 Hz, 1H), 4.75 (br s, 1H), 3.62 (br s, 1H), 2.50-2.57-2.31 (m, 1H), 2.31 (dt, J=13.2, 6.7 Hz, 1H), 1.66-1.85 (m, 1H), 1.45 (br s, 3H), 1.11 (br s, 6H), 0.87 (dt, J=8.6, 5.8 Hz, 1H), 0.66 (br s, 1H).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])=[CH:11][CH:10]=2)=CC=1>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])=[CH:11][CH:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ccc(C(C)(C)C#N)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C#N)c1ccc(N)nc1
Temperature: 25 °C
Yield: 290.8 %

Procedure:
A solution of 156b (514 mg, 1.28 mmol) in CF3COOH (15 mL) was stirred at 60° C. for 2 h. After this time the reaction was cooled to room temperature. It was then evaporated under reduced pressure and residue was washed with petroleum ether and ethyl acetate to afford 156c (600 mg, crude) as a yellow solid. MS-ESI: [M+H]+ 162.3
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.O=[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][NH:9][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCc1cccc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NCc2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of (3-bromophenyl)methanamine (670 mg, 3.6 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (600 mg, 3 mmol) and sodium triacetoxyborohydride (1.27 g, 6 mmol) in 10 mL of dichloromethane was added acetic acid (360 mg, 6 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, eluting with petroleum ether:EtOAc=3:1) to give tert-butyl 4-(3-bromobenzylamino)piperidine-1-carboxylate (0.9 g, 68%) as an oil. 1H NMR (300 MHz, CDCl3) δ 7.48-7.47 (m, 1H), 7.38-7.35 (m, 1H), 7.25-7.17 (m, 2H), 4.10 (brs, 1H), 3.79 (s, 2H), 2.85-2.76 (m, 2H), 2.67-2.61 (m, 1H), 1.87-1.82 (m, 2H), 1.45 (s, 9H), 1.37-1.29 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[OH:16])([O-])=O>CO>[NH2:1][C:4]1[CH:12]=[C:11]([NH2:13])[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[OH:16]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O
Solvent: CO
Product: Nc1cc(N)c(O)c(C(=O)O)c1
Temperature: 85 °C
Reaction time: 14 h
Yield: 117.3 %

Procedure:
In an autoclave, 20 g of the crude DNSA produced in the above Production Example 4 was dissolved in 150 mL methanol. The solution was degassed by purging nitrogen for 10 minutes, and slowly added with 19.5 g of 98% conc. sulfuric acid and then added with 250 mg of catalyst Pd/C. The autoclave was sealed and bubbled with hydrogen at a pressure of 7 kg/cm2 for further reacting about 12 to 16 hours. After hydrogen was no longer consumed, the pressure in the autoclave was released to normal pressure and the suspended solid in the autoclave was taken out and filtered. The resultant solid was mixed with 600 g of pure water and heated at 85° C. to allow solid dissolving completely. The resultant solution was hot filtered to filter the hydrogenation catalyst off. The filtered solution was distilled under reduced pressure with recovery pure water until all solids were solidified. The solid was added with 450 mL iso-propanol to subject to recrytalization to obtain 17.3 g of product 3,5-diaminoalicylic acid (DASA), m.p.=246.7° C.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][C@:26]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29][NH:28][CH2:27]2)[CH2:19][CH2:18]1)[CH3:4].[CH3:37][O:38][C:39]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][CH2:50][O:51][CH3:52])=[CH:44][C:40]=1[C:41](O)=[O:42].CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl>[CH2:3]([O:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][C@:26]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29][N:28]([C:41]([C:40]3[CH:44]=[C:45]([O:48][CH2:49][CH2:50][O:51][CH3:52])[CH:46]=[CH:47][C:39]=3[O:38][CH3:37])=[O:42])[CH2:27]2)[CH2:19][CH2:18]1)[CH3:4]
Reactant: COCCOc1ccc(OC)c(C(=O)O)c1
Reactant: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(OCCOC)ccc4OC)C3)CC2)nc2ccccc21
Yield: 79.6 %

Procedure:
Stir a mixture of 1-(2-ethoxy-ethyl)-2-{4-[2-((S)-3-phenyl-pyrrolidin-3-yl)-ethyl]-[1,4]diazepan-1-yl}-1H-benzoimidazole dihydrochloride (0.32 g, 0.6 mmol, Preparation 12.1), 2-methoxy-5-(2-methoxy-ethoxy)-benzoic acid (0.16 g, 0.72 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.14 g, 0.72 mmol), 1-hydroxybenzotriazole hydrate (0.097 g, 0.72 mmol), diisopropyoethylamine (0.2 mL, 1.2 mmol) and dichloromethane (20 mL) overnight at room temperature. Dilute the reaction mixture with dichloromethane, wash with saturated brine, dry (MgSO4) the organic phase, filter and concentrate the filtrate in vacuo. Purify the residue by column chromatography on silica gel eluting sequentially with ethyl acetate, 5% methanol in dichloromethane and 10% methanol in dichloromethane. Concentrate the appropriate fractions to afford 0.32 g of the title compound, Rf=0.46 (silica gel, 10% methanol in dichloromethane). The compound may be converted to the dihydrochloride salt by methods well known in the art.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Br-].[CH3:7][O:8][C:9](=[O:28])[CH2:10][C:11]1([CH3:27])[C:16]2=[CH:17][CH:18]=[CH:19][N:15]2[C:14]2[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:13]=2[O:12]1>>[CH3:7][O:8][C:9](=[O:28])[CH2:10][C:11]1([CH3:27])[C:16]2=[CH:17][CH:18]=[C:19]([Cl:4])[N:15]2[C:14]2[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:13]=2[O:12]1
Reactant: COC(=O)CC1(C)Oc2ccc([N+](=O)[O-])cc2-n2cccc21
Reactant: O=S(=O)(Cl)Cl
Agent: [Br-]
Product: COC(=O)CC1(C)Oc2ccc([N+](=O)[O-])cc2-n2c(Cl)ccc21

Procedure:
By following the procedure of Example 75 but using as a starting material the appropriate starting material of formula 3, for example those described in Examples 2 to 41 or the appropriate starting material of formula 1, for example, those described in Examples 42 to 69, together with the appropriate nucleophilic reagent, for instance, sulfuryl chloride or bromide, respective compounds of formulae 3 and 1 in which R2 is halogen are obtained. More specifically exemplified, the use of 4-methyl-8-nitro-4H-pyrrolo-[2,1-c][1,4]benzoxazine-4-acetic acid methyl ester, described in Example 2 gives 1-chloro-4-methyl-8-nitro-4H-pyrrolo[2,1-c][1,4]-benzoxazine-4-acetic acid methyl ester, m.p. 124° - 125° C.
Reaction SMILES: CC1(C)[O:7][CH2:6][CH:5]([C:8]2[CH:32]=[CH:31][C:11]([O:12][CH2:13][C:14]3[N:15]=[C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]5[N:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH2:21][CH2:20]4)[S:17][CH:18]=3)=[CH:10][CH:9]=2)[CH2:4][O:3]1>CC(C)=O.Cl>[N:30]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[N:22]1[CH2:21][CH2:20][CH:19]([C:16]2[S:17][CH:18]=[C:14]([CH2:13][O:12][C:11]3[CH:10]=[CH:9][C:8]([CH:5]([CH2:6][OH:7])[CH2:4][OH:3])=[CH:32][CH:31]=3)[N:15]=2)[CH2:24][CH2:23]1
Reactant: CC1(C)OCC(c2ccc(OCc3csc(C4CCN(c5ncccn5)CC4)n3)cc2)CO1
Agent: Cl
Solvent: CC(C)=O
Product: OCC(CO)c1ccc(OCc2csc(C3CCN(c4ncccn4)CC3)n2)cc1
Temperature: 27 °C
Reaction time: 12 h
Yield: 117.2 %

Procedure:
To a solution of 4-((4-(2,2-dimethyl-1,3-dioxan-5-yl)phenoxy)methyl)-2-(1-(pyrimidin-2-yl)piperidin-4-yl)thiazole (500 mg, 0.0010 moles) in acetone (20 ml), conc. HCl (2 ml) was added portion-wise and the reaction mixture was stirred for 12 hours at 27° C. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The organic layer was successively washed with water & brine, dried over sodium sulfate and evaporated under reduced pressure to yield 500 mg product as white solid
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[C:12]=2[CH:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:27][CH:26]=2)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[C:12]=2[CH2:23][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]3)=[CH:27][CH:26]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: COc1ccc2c(C(O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 675.1 %

Procedure:
Dissolve the compound of Example 76 (185.2 mg, 0.33 mmol), Et3SiH (0.3 mL, 1.88 mmol) and TFA (0.3 mL, 3.8 mmol) in CH2Cl2 (30 mL). Stir at room temperature for 1 hour. Quench with saturated aqueous NaHCO3 and extract with 25% i-PrOH in CH2Cl2. Dry over Na2SO4, filter and concentrate. Purify the crude material by flash chromatography (0-5% MeOH/CH2Cl2 to afford 1.18 g of the title compound (63%). LCMS: m/z=530 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[S:30]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cc(C(=O)N2CCNCC2)cc(OC)c1OC
Solvent: c1ccccc1
Product: COc1cc(C(=S)N2CCNCC2)cc(OC)c1OC
Yield: 61.5 %

Procedure:
A mixture of 1-(3,4,5-trimethoxybenzoyl)piperazine (2.0 g), a Lawesson reagent ([2,4-bis(4-methoxypehnyl)-1,3-dithia-2,4-diphosphethane-2,4-disulfide]) (2.9 g) and benzene (20 ml) is heated under reflux for 30 minutes. After cooling, insolubles are filtered off, and the filtrate is concentrated under reduced pressure. To the residue is added 1N hydrochloric acid (100 ml) and following ethyl acetate (50 ml), and the mixture is shaken. The aqueous layer is separated, and to the aqueous layer is added a 1N aqueous solution of sodium hydroxide to make the system alkaline, followed by extraction with methylene chloride. The organic layer is washed with water and dried, then the solvent is distilled off. The residue is recrystallized from ethyl acetate - hexane to afford 1-(3,4,5-trimethoxythiobenzoyl)piperazine as pale yellow prisms (1.3 g), m.p. 116°-118° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:13][C:14](=[O:25])[CH2:15][CH2:16][C:17]1([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]1)([CH3:12])([CH3:11])[CH3:10].[CH3:26][O:27][CH2:28][CH2:29]I>O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C.COCCOC.CCCCCCC>[C:9]([O:13][C:14]([CH:15]([CH2:29][CH2:28][O:27][CH3:26])[CH2:16][C:17]1([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:25])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)CCC1(C(=O)O)CCCC1
Reactant: COCCI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COCCOC
Solvent: CCc1ccccc1
Product: COCCC(CC1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
To a solution of commercially supplied lithium diisopropylamide (9.63 kg of a 2M solution in tetrahydrofuran/n-heptane/ethylbenzene, 23.7 mol) in 1,2-dimethoxyethane (25 L) at −10° C. under an atmosphere of N2 was added a solution of 1-(3-tert-butoxy-3-oxopropyl)cyclopentane carboxylic acid (EP274234B1—see Example 35) (2.5 kg, 10.3 mol) in 1,2-dimethoxyethane (12.5 L) with stirring over a period of 4 hours whilst maintaining the reaction temperature at −10° C. The header tank was washed with 1,2-dimethoxyethane (2.5 L) and this was added to the reaction. The reaction mixture was then allowed to stir at −10° C. for 1.75 hours. To the resultant solution was added a solution of 2-iodoethyl methyl ether (2.73 kg, 14.4 mol) in 1,2-dimethoxyethane (10 L) over a period of 1.75 hours. The reaction was then stirred at this temperature for 4 hours before warming to 20° C. over a period of 4 hours. After stirring at this temperature for 8 hours the reaction was quenched by the addition of aqueous ammonium chloride (25 L of a 2.8 M solution), ethyl acetate (12.5 L) was then added. Aqueous hydrochloric acid (10 L of 5 M solution) was then added with stirring to adjust the pH to between 2 and 3. The two phases were mixed and then separated. The organic phase was then extracted three times with aqueous potassium carbonate solution (0.3 M solution; 37.5 L, 12.5 L and then 6.25 L). To the combined aqueous phases was then added n-heptane (15.6 L), and aqueous hydrochloric acid (14.5 L of a 5 M solution) with stirring until the pH of the aqueous layer was between 2 and 3. The layers were then separated and the aqueous phase was extracted with n-heptane (15.6 L). The combined organic phases were then washed with saturated brine (3.1 L) and were then concentrated under vacuum to give the crude title compound (2.50 kg, 8.32 mol, 81% yield) as a solution in n-heptane (21.8 kg total solution weight).