Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][NH2:17])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>ClCCl>[C:32]1([O:31][C:29](=[O:30])[NH:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13][C:10]2[CH:11]=[CH:12][C:7]3[N:8]([C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]=3)[CH:9]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)c1nnc2ccc(Sc3ccccc3CN)cn12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1nnc2ccc(Sc3ccccc3CNC(=O)Oc3ccccc3)cn12
Reaction time: 0.33 h

Procedure:
To a solution of 2-(3-Isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylsulfanyl)-benzylamine (417 mg, 1.4 mmol) in dichloromethane (14 mL) at ambient temperature under nitrogen was added pyridine (226 μL, 2.8 mmol) and phenyl chloroformate (192 μL, 1.5 mmol). The reaction was stirred for 20 minutes, then quenched with saturated NaHCO3. The reaction mixture was extracted with dichloromethane, the combined organics washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography (eluting with ethyl acetate), followed by ether/hexane trituration gave the above named compound as a white solid (526 mg, 90%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.S1C=CC=C1C(Cl)=O.[CH2:31](Cl)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[N:13]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3cccs3)c2CC1
Agent: O=C(Cl)c1cccs1
Product: c1ccc(Cn2nc(-c3cccs3)c3c2CCNCC3)cc1

Procedure:
The title compound (28 mg) was prepared from 3-thiophen-2-yl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester as described in Example 103, using thiophene-2-carbonyl chloride (5 mmol) in place of 4-chlorobenzoyl chloride, and benzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C18H19N3S, 309.13; found, m/z 310.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.27-7.01 (m, 8H), 5.28 (s, 2H), 3.26-3.24 (br m, 2H), 3.18-3.16 (br m, 2H), 3.11-3.09 (br m, 2H), 2.96-2.94 (br m, 2H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[N:5][CH:4]=1)#[N:2].[NH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][OH:24]>>[C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([NH:21][C@@H:22]([CH2:25][CH3:26])[CH2:23][OH:24])=[O:18])=[CH:13][CH:14]=2)[CH:6]=[N:5][CH:4]=1)#[N:2]
Reactant: CCC(N)CO
Reactant: CC(C)(C(=O)O)c1ccc(-c2cncc(C#N)n2)cc1
Product: CC[C@@H](CO)NC(=O)C(C)(C)c1ccc(-c2cncc(C#N)n2)cc1
Yield: 37 %

Procedure:
Prepared in a similar manner to Example 20 from 2-(4-(6-Cyanopyrazin-2-yl)phenyl)-2-methylpropanoic acid (example 20a) and 2-aminobutan-1-ol. Yield 37%.
Reaction SMILES: ClC(N(C)C)=C(C)C.[Cl:9][C:10]1[C:15]([CH2:16][NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=[C:12]([Cl:24])[C:11]=1[NH:25][C:26]1[N:30]([CH3:31])[C:29]2[CH:32]=[C:33]([O:39][CH2:40][CH:41]([F:43])[F:42])[C:34]([C:36]([OH:38])=O)=[CH:35][C:28]=2[N:27]=1.[Cl:44][C:45]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:46]=1[NH2:47].N1C=CC=CC=1>C(#N)C>[Cl:44][C:45]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:46]=1[NH:47][C:36]([C:34]1[C:33]([O:39][CH2:40][CH:41]([F:42])[F:43])=[CH:32][C:29]2[N:30]([CH3:31])[C:26]([NH:25][C:11]3[C:12]([Cl:24])=[CH:13][CH:14]=[C:15]([CH2:16][NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])[C:10]=3[Cl:9])=[N:27][C:28]=2[CH:35]=1)=[O:38]
Reactant: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)O)c(OCC(F)F)cc21
Reactant: Nc1ccc(Cl)cc1Cl
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: CC#N
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)Nc3ccc(Cl)cc3Cl)c(OCC(F)F)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(1-Chloro-2-methyl-propenyl)-dimethylamine (20 μl) is added to a mixture of 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid (53 mg, 0.10 mmol) in 1.0 mL acetonitrile and it is stirred 15 min at rt. The crude acid chloride solution is added to a mixture of 2,4-dichloroaniline (16 mg, 0.10 mmol), pyridine (24 μL, 0.30 mmol) and acetonitrile (1.0 mL) and it is stirred over the weekend at 60° C. The solvent is removed in vacuo and the residue is dissolved in 2 mL of a 9:1 DMF/water-solution and is purified via preparative HPLC.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.COC1C=CC(C2C=CC3C(=CC=CC=3)N=2)=CC=1>CN(C)C=O.COCCOC>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(O)cc1
Reactant: Clc1ccc2ccccc2n1
Agent: COc1ccc(-c2ccc3ccccc3n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc3ccccc3n2)cc1
Temperature: 5 °C

Procedure:
To a stirred suspension of 32 g. sodium hydride (52% suspension in mineral oil) in 475 ml. dimethylformamide and 475 ml. 1,2-dimethoxyethane was added, portionwise during about fifteen minutes, 59.5 g. 4-methoxyphenol followed by, after five minutes, a solution of 95.5 g. 2-chloroquinoline in 130 ml. dimethyl formamide in one portion and the resulting mixture was heated under reflux for sixteen hours, cooled to 5° C., poured into 4000 ml. ice-water and extracted with ether. The ether extract was washed with ice cold 2% aqueous sodium hydroxide solution, water and saturated salt solution, dried and evaporated to dryness under reduced pressure. The resulting crystals were recrystallized from benzene-hexane to give 104 g. 2-(4-methoxyphenyl)quinoline; m.p. 96.5°-98° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:11]([NH2:12])=[C:10]([C:13]([O:15]C)=[O:14])[S:9][N:8]=2)[CH:2]=1.C(O)C.[OH-].[Na+].Cl>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:11]([NH2:12])=[C:10]([C:13]([OH:15])=[O:14])[S:9][N:8]=2)[CH:2]=1
Reactant: COC(=O)c1snc(-c2cccnc2)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1c(-c2cccnc2)nsc1C(=O)O
Temperature: 0 °C

Procedure:
A solution of 1.8 g. of methyl 3-(3-pyridyl)-4-amino-5-isothiazolecarboxylate in 20 ml. of ethanol and 20 ml. of water containing three pellets of sodium hydroxide was heated at reflux for ninety minutes. The reaction mixture was then added to 50 ml. of ice water, and the aqueous mixture was acidified by the addition of 1 N aqueous hydrochloric acid. The solid precipitate was collected by filtration and recrystallized from acetic acid and water to provide 3-(3-pyridyl)-4-amino-5-isothiazolecarboxylic acid. M.P. 235°-236° C.
Reaction SMILES: C([Li])CCC.C([Mg]Cl)CCC.[F:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][C:19](I)=[CH:18]2.[C:24]([C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=[O:31])([CH3:27])([CH3:26])[CH3:25].Cl>O1CCCC1>[C:24]([C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]([C:19]1[CH:20]=[N:21][C:22]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[F:12])[OH:31])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccccc1C=O
Reactant: Fc1cccc2cc(I)cnc12
Agent: CCCC[Mg]Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1C(O)c1cnc2c(F)cccc2c1
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
After 3 ml of tetrahydrofuran was cooled to −10° C., 0.91 ml of n-butyllithium (2.6 M hexane solution) and 1.35 ml of n-butylmagnesium chloride (0.91 M tetrahydrofuran solution) were added. After 30 minutes of stirring, 0.98 g of 8-fluoro-3-iodoquinoline was added and the mixture was stirred for 15 minutes. 0.49 g of 2-t-butylbenzaldehyde was added to the reaction solution and the mixture was stirred for 3 hours. After dilute hydrochloric acid was added to the reaction mixture, the liquid was separated with ethyl acetate. After the organic layer was concentrated and purified by silica gel column chromatography, 0.55 g of (2-t-butyl-phenyl)-(8-fluoro-quinolin-3-yl)-methanol (Compound Number 54) was obtained.
Reaction SMILES: C(C1C=CC2CCC3C=C(C[Br:18])C=CC=3SC=2C=1)#N.[C:20]([C:22]1[CH:23]=[CH:24][C:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[C:35]([CH2:36]O)[C:28]=3[S:27][C:26]=2[CH:38]=1)#[N:21]>>[C:20]([C:22]1[CH:23]=[CH:24][C:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[C:35]([CH2:36][Br:18])[C:28]=3[S:27][C:26]=2[CH:38]=1)#[N:21]
Reactant: N#Cc1ccc2c(c1)Sc1c(CO)cccc1CC2
Reactant: N#Cc1ccc2c(c1)Sc1ccc(CBr)cc1CC2
Product: N#Cc1ccc2c(c1)Sc1c(CBr)cccc1CC2
Yield: 95 %

Procedure:
As described previously for the 3-cyano-8-bromomethyl-10,11-dihydrodibenzo[b,f]thiepin, the title compound was prepared from 3-cyano-6-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin in 95% yield.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](Cl)=[O:8])[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.[CH:14]1([C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[NH2:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[CH:14]1([C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[NH:22][C:7]([C:5]2[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3][N:2]([CH3:1])[CH:6]=2)=[O:8])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: Nc1ccccc1C1CCCCC1
Reactant: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(C(=O)Nc2ccccc2C2CCCCC2)c(C(F)(F)F)n1
Reaction time: 8 h
Yield: 111.3 %

Procedure:
To 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid chloride (1.6 g) in CH2Cl12 (25 mL) at 0° C. was added dropwise a solution of 2-cyclohexylaniline (1.3 g) and triethylamine (1.0 mL) in CH2Cl2 (25 mL). The contents were stirred overnight, coming to RT. The contents were washed with water, 2N HCl (2×100 mL), dried (MgSO4) and concentrated in vacuo leaving an amber foam (2.9 g). Crystallization from EtOAc/hexane gave the desired amide as white crystals (1.2 g). Most of the compounds of the present invention were made via this coupling procedure.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=O)[CH2:4][O:3][CH2:2]1.[NH2:9][CH2:10][CH2:11][CH2:12][OH:13]>>[OH:13][CH2:12][CH2:11][CH2:10][N:9]1[C:1](=[O:8])[CH2:2][O:3][CH2:4][C:5]1=[O:7]
Reactant: NCCCO
Reactant: O=C1COCC(=O)O1
Product: O=C1COCC(=O)N1CCCO

Procedure:
A solution of diglycolic anhydride (2.32 g, 2/mmol) in 3-amino-1-propanol (6 ml) was refluxed a 180° C. for 3 hours. The volatiles were removed by evaporation a nd the residue was purified by column chromatography on silica eluting with methylene chloride/methanol (8/2) to give 4-(3-hydroxypropyl)-3,5-dioxomorpholine (3(46 g, 99%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH:13](=[O:17])[CH2:14][CH2:15][CH3:16].[NH4+].[Cl-]>C(OCC)C.O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:13]([OH:17])[CH2:14][CH2:15][CH3:16]
Reactant: Brc1ccccn1
Reactant: CCCC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CCCC(O)c1ccccn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromopyridine (1.1 g, 6.96 mmol, purchased from Sigma-Aldrich) in diethyl ether (8 mL) at −78° C. under N2 was added butyllithium (3.1 mL×2.5 M) over 10 min. The reaction solution was stirred at −78° C. for 1.0 hr. To the mixture was added butyraldehyde (0.602 g, 8.35 mmol, purchased from Sigma-Aldrich) dropwise over 10 min. After stirring at −78° C. for 15 min, the mixture was allowed to warm to rt and stirred at rt for 1.5 hr. The reaction mixture was poured into saturated aqueous NH4Cl solution (10 mL), diluted with water (15 mL), and extracted with EtOAc (20 mL×3). The organic layers were combined, washed with water, sat. aq. NaCl solution, and dried over MgSO4. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel with 20-80% EtOAc/Hexanes provided the title compound as a white solid. Mass Spectrum (ESI) m/z=152.1 (M+1).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][C:26]([NH2:28])=[O:27])[CH:23]=2)[NH:18][CH:17]=1.[CH3:29]I.O>CN(C)C=O>[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][C:26]([NH2:28])=[O:27])[CH:23]=2)[N:18]([CH3:29])[CH:17]=1
Reactant: CI
Reactant: NC(=O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(CCN2C(=O)c3ccccc3C2=O)c2cc(CC(N)=O)ccc21
Reaction time: 0.5 h

Procedure:
Sodium hydride (80% dispersion in oil) (0.14 g) was added to a solution of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indole-5-acetamide (1.5 g) in dry dimethylformamide (10 ml). After stirring the red solution for 30 min, methyl iodide (0.41 ml) was added and the mixture was stirred for a further 16 h. Water (40 ml) was added, the solid collected by filtration and crystallised from propan-2-ol to give the title compound as a yellow powder (1.25 g), m.p. 200°-2° C.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[O:12][C:13]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:14]=3[C:15]=2[C:16](=[O:29])[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)[CH:8]=[N:7]1)C.[OH-].[Na+:38]>C1COCC1.O>[CH3:35][O:34][C:32]1[CH:31]=[CH:30][C:14]2[C:15]([C:16](=[O:29])[C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[C:11]([C:9]3[CH:8]=[N:7][N:6]([CH2:5][C:4]([O-:36])=[O:3])[CH:10]=3)[O:12][C:13]=2[CH:33]=1.[Na+:38]
Reactant: CCOC(=O)Cn1cc(-c2oc3cc(OC)ccc3c2C(=O)c2cc(OC)c(OC)c(OC)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(-c3cnn(CC(=O)[O-])c3)oc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a stirred solution of {4-[6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-benzofuran-2-yl]-pyrazol-1-yl}-acetic acid ethyl ester (25 mg, 0.051 mmol) in a mixture of THF (1 mL) and water (1 mL) was added sodium hydroxide (70 mg, 1.75 mmol) and the reaction allowed to stir overnight at ambient temperature. After this time the reaction was concentrated under vacuum and the residue dissolved in water (20 mL) and washed with diethyl ether (5 mL). The aqueous layer was acidified to pH 1-2 with concentrated hydrochloric acid and extracted with ethyl acetate (2×15 mL). The combined organic layers were concentrated under vacuum, the residue was dissolved in methanol (2 mL) and the resulting solution was treated with a methanolic solution of sodium methoxide until a pH of 9 was obtained. The solvent was removed under vacuum and the resulting yellow solid was washed with small portions of cold diethyl ether and isopropanol to provide the title compound (22 mg, 89%). 1H-NMR (D2O) δ 7.48 (s, 1H), 7.28 (s, 1H), 6.68-6.60 (m, 2H), 6.60 (s, 2H), 6.28 (d, J=7.6 Hz, 1H), 4.49 (s, 2H), 3.61 (s, 3H), 3.49 (s, 3H), 3.39 (s, 6H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([Si:12]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[O:13][CH:14]1[CH:17]([CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH:15]1[OH:37])([CH3:11])[CH3:10].[CH3:50][S:51](Cl)(=[O:53])=[O:52]>C(Cl)Cl>[CH3:50][S:51]([O:37][CH:15]1[CH2:16][CH:17]([CH2:18][O:19][Si:20]([C:33]([CH3:34])([CH3:35])[CH3:36])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:14]1[O:13][Si:12]([C:9]([CH3:8])([CH3:10])[CH3:11])([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)(=[O:53])=[O:52]
Reactant: CC(C)(C)[Si](OCC1CC(O)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCC1CC(OS(C)(=O)=O)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 59.8 %

Procedure:
Freshly distilled triethylamine (1.28 g, 8.2 mmol) was dissolved in 75 mL of freshly distilled methylene chloride. To this solution was added 2.3 g (3.9 mmol) of 2-O-((1,1-dimethylethyl)diphenylsilyl)-3-(((1,1-dimethylethyl)diphenyl-silyl)oxymethyl)-1,2-cyclobutanediol from Step K and the resultant solution was cooled to -78° C. with stirring, under a nitrogen atmosphere. Methanesulfonyl chloride (0.99 g, 8.2 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 3.5 h, the reaction mixture was diluted with 125 mL of methylene chloride and this solution was washed with 100 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue (2.9 g) was dissolved in 25 mL of 10% acetone in hexane and purified on a 2.5×45 cm silica gel column eluted at 2 psi with 500 mL of 5% acetone in hexane, followed by 250 mL of 10% acetone in hexane, to give 1.57 g (60% yield) of the title compound; MS DCI-NH3M/Z: 690 (M+NH4)+ ; 1H NMR (CDCl3) δ 1.95 (m, 1H), 2.20 (m, 1H), 2.77 (m, 1H), 2.90 (s, 3H), 3.39 (d, 2H), 4.39 (m, 1H), 4.88 (m, 1H), 7.30-7.54 (m, l5H), 7.60-7.70 (m, 5H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.CCN(C(C)C)C(C)C.[C:24]1([NH:30][CH2:31][CH2:32][NH2:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=[C:2]([NH:33][CH2:32][CH2:31][NH:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1
Reactant: NCCNc1ccccc1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(NCCNc2ccccc2)nc(N2CCOCC2)n1
Temperature: 75 °C
Reaction time: 20 h

Procedure:
To a solution of 4-(4,6-dichloropyrimidin-2-yl)morpholine (prepared as described in Method 22; 932 mg, 4.0 mmol) and DIEA (0.7 mL, 4.0 mmol) in ACN (40 mL), neat N1-phenyl-ethane-1,2-diamine (0.523 mL, 4.0 mmol) was slowly added. The reaction mixture was stirred at 70-80° C. under nitrogen. After 20 hours, the reaction mixture was cooled down, and the solvent was removed under reduced pressure. The crude product was partitioned between EtOAc (120 mL) and 0.1 M NaHCO3 (50 mL). The organic layer was washed with additional 0.1 M NaHCO3 (2×50 mL), brine (50 mL), dried, filtered and concentrated to give N1-(6-chloro-2-morpholinopyrimidin-4-yl)-N2-phenylethane-1,2-diamine, as an off-white solid (1.29 g, 96%). LC/MS (m/z): 334.0 (MH+), Rt 1.94 minutes.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34]C)[CH:28]=1>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CCOc1cccc(OCCCBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: COc1cccc(OCCCOc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3O)cc2)c1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.808 g of 1-(3-bromopropoxy)-3-ethoxybenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.30 (1:2 EtoAc-heptane); Rt=5.18.
Reaction SMILES: [C:1]([CH:4]1[C:9](=O)[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:6][C:5]1=[O:19])(=O)[CH3:2].O.[NH2:21][NH2:22]>C(O)C>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:7]1[CH2:8][C:9]2[NH:22][N:21]=[C:1]([CH3:2])[C:4]=2[C:5](=[O:19])[CH2:6]1
Reactant: NN
Reactant: COc1ccccc1C1CC(=O)C(C(C)=O)C(=O)C1
Solvent: O
Solvent: CCO
Product: COc1ccccc1C1CC(=O)c2c(C)n[nH]c2C1
Yield: 782 %

Procedure:
A solution of 2-acetyl-5-(2-methoxyphenyl)cyclohexane-1,3-dione (0.10 g) and hydrazine hydrate (0.21 g) in ethanol (20 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give colorless crystals of 6-(2-methoxyphenyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.77 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=2[CH2:19][CH2:20][CH3:21])=[N:5][N:6]=1.[C:22]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)(=[O:27])[CH2:23][C:24]([O-])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:8][S:7][C:4]2[S:3][C:2]([NH:1][C:24](=[O:25])[CH2:23][C:22]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[O:27])=[N:6][N:5]=2)=[C:10]([CH2:19][CH2:20][CH3:21])[C:11]=1[OH:18])(=[O:17])[CH3:16]
Reactant: COc1ccc(COC(=O)CC(=O)[O-])cc1
Reactant: CCCc1c(CSc2nnc(N)s2)ccc(C(C)=O)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCc1c(CSc2nnc(NC(=O)CC(=O)OCc3ccc(OC)cc3)s2)ccc(C(C)=O)c1O
Yield: 17.4 %

Procedure:
To a solution of 0.14 g of 2-amino-5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazole obtained in Example 5 and 0.15 g of mono-p-methoxybenzyl malonate in 3 ml of pyridine were added 0.15 g of dicyclohexylcarbodiimide and a catalytic amount of p-toluenesulfonic acid. The resultant mixture was stirred at room temperature for 6 hours. During the stirring, 0.15 g each of mono-p-methoxybenzyl malonate and dicyclohexylcarbodiimide were supplemented to the system. After completion of the reaction, ethyl acetate was added to the system. After insoluble matters were filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in chloroform. The solution was washed with, in sequence, 1N hydrochloric acid, water, a saturated aqueous sodium bicarbonate solution and water and then, dried over anhydrous magnesium sulfate. The solvent was then removed by distillation. The resultant residue was subjected to silica gel column chromatography followed by elution with a mixture of chloroform-methanol (4:1). The eluate was recrystallized from isopropyl alcohol to give 0.04 g of p-methoxybenzyl 3-[[ 5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]amino]-3-oxopropionate.
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[O:20]=[C:21]1[O:25][C@H:24]([C:26]([OH:28])=O)[CH2:23][CH2:22]1.CCN=C=NCCCN(C)C.[NH2:40][C@@H:41]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43][C@H:42]1[NH:50][C:51]([C:53]1[NH:57][C:56]2[S:58][C:59]([Cl:61])=[CH:60][C:55]=2[CH:54]=1)=[O:52]>C(Cl)Cl>[Cl:61][C:59]1[S:58][C:56]2[NH:57][C:53]([C:51]([NH:50][C@@H:42]3[CH2:43][C:44]4[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=4)[C@H:41]3[NH:40][C:26]([C@@H:24]3[CH2:23][CH2:22][C:21](=[O:20])[O:25]3)=[O:28])=[O:52])=[CH:54][C:55]=2[CH:60]=1
Reactant: O=C1CC[C@@H](C(=O)O)O1
Reactant: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)sc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CC[C@@H](C(=O)N[C@@H]2c3ccccc3C[C@H]2NC(=O)c2cc3cc(Cl)sc3[nH]2)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
DIPEA (180 μL, 1.05 mmol), HOBT (68 mg, 0.5 mmol), (2S)-5-oxotetrahydrofuran-2-carboxylic acid (CAS Reg. No: [21461–84–7], 0.5 mmol, 65 mg) and EDAC (120 mg, 0.63 mmol) were added to a suspension of N-[(1R,2R)-1-amino-2,3-dihydro-1H-inden-2-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Method 21, 223 mg, 0.5 mmol) in anhydrous DCM (7 mL). The reaction was stirred at ambient temperature for approximately 16 h. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in EtOAc (5 mL), washed with water (2×5 mL), brine (10 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure and the residue triturated (EtOAc:hexane, 1:10), collected by filtration, washed with hexane (2×5 mL) and dried to give the title compound (112 mg, 56%) as a brown solid.