Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][C:8]3([CH2:14][CH2:13][N:12]([CH:15]([C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:34]=[C:33]6[C:28]([CH:29]=[CH:30][CH:31]=[N:32]6)=[CH:27][CH:26]=5)=[CH:21][CH:20]=4)[C:16]([OH:18])=O)[CH2:11][CH2:10]3)[O:7][CH2:6][C:5]2=[O:35])[CH2:3][CH2:2]1.Cl.[CH3:37][N:38](C)CCCN=C=NCC.CN>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]1([N:4]2[CH2:9][C:8]3([CH2:14][CH2:13][N:12]([CH:15]([C:19]4[CH:20]=[CH:21][C:22]([C:25]5[CH:34]=[C:33]6[C:28]([CH:29]=[CH:30][CH:31]=[N:32]6)=[CH:27][CH:26]=5)=[CH:23][CH:24]=4)[C:16]([NH:38][CH3:37])=[O:18])[CH2:11][CH2:10]3)[O:7][CH2:6][C:5]2=[O:35])[CH2:3][CH2:2]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)C(c1ccc(-c2ccc3cccnc3c2)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)C(c1ccc(-c2ccc3cccnc3c2)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reaction time: 0.17 h
Yield: 26 %

Procedure:
A solution of 2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(4-(quinolin-7-yl)phenyl)acetic acid (0.191 mmol) in dichloromethane (2 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.286 mmol) and 4-(dimethylamino)pyridine (0.763 mmol) at room temperature. After stirring for 10 minutes, this mixture was treated with methanamine (2M in THF) (0.400 mmol). The reaction vessel was sealed and the reaction was allowed to stir at room temperature for 16 hours. At this point an additional portion of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.15 mmol) and methanamine (2M in THF) (0.400 mmol) was added and the solution was allowed to stir at room temperature for 3 hours. The reaction was concentrated under a nitrogen stream. Purification of the residue by reverse phase HPLC (5-35% acetonitrile with 0.1% TFA/water with 0.1% TFA) and then by silica gel chromatography (0-9% methanol/dichloromethane) followed by lyophilization from water with 10% acetonitrile (1 mL) afforded the title compound (26%) as a white solid. MS(ES)+ m/e 485.4 [M+H]+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.B([O-])=[O:11].[Na+:13]>>[OH-:7].[Na+:13].[OH-:11].[Na+:13].[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=B[O-]
Agent: C=O
Agent: [Na+]
Solvent: Oc1ccccc1
Product: [OH-]

Procedure:
A reactor equipped as in Examples A and B was charged with phenol and formaldehyde in a formaldehyde to phenol molar ratio (F/P) of about 1.5:1. The formaldehyde was charged as a 50% aqueous solution. About 3% by weight based on the total charge of sodium metaborate was added and sufficient 50% aqueous sodium hydroxide to give a mole ratio (NaOH/phenol) of about 0.054:1. The mixture was heated to about 65° C. and held until the free formaldehyde fell to less than about 1.75%. The mixture was cooled to about 55° C. and distilled under vacuum to a non-volatile solids content of about 65%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][O:24][CH2:25][CH3:26]>CN(C=O)C>[CH2:25]([O:24][CH2:23][O:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1)[CH3:26]
Reactant: CCOCCl
Reactant: CCOC(=O)c1cnc2cc(O)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCOc1ccn2c(C(=O)OCC)cnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
Ethyl 7-hydroxyimidazo[1,2-a]pyridine-3-carboxylate (100 mg, 0.38 mmol) was dissolved in DMF (3 mL) and treated with potassium carbonate (79 mg, 0.57 mmol). The mixture was stirred at ambient temperature for 30 minutes before adding chloromethylethyl ether (40 mg, 0.42 mmol) and heating mixture to 60° C. for 1 hour. The crude mixture was purified by reverse phase chromatography to give ethyl 7-(ethoxymethoxy)imidazo[1,2-a]pyridine-3-carboxylate (11 mg).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:25]([F:28])([F:27])[F:26])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)CO.O.NN.[OH-].[K+]>O>[CH2:7]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:25]([F:28])([F:26])[F:27])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: FC(F)(F)c1cccc2c(-c3ccccc3)c(Cc3ccccc3)cnc12
Temperature: 120 °C
Yield: 54.2 %

Procedure:
Phenyl[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone (Example 1, 0.244 g, 0.65 mmol) was taken into ethylene glycol (5 mL) along with hydrazine hydrate (0.3 mL) and heated at 120° C. for 2 hours. Next, a few pellets of KOH were added and reaction was heated at 180° C. for 4 hours. The reaction was allowed to cool to room temperature, where water was added and the mixture was extracted with ether and concentrated. The resulting material was purified via column chromatography using 5% ethyl acetate in hexane as the eluent to produce 0.128 g of desired product. MS (ESI) m/z 364 ([M+H]+); 1H NMR (CDCl3) δ 9.01 (s, 1H), 8.02 (d, J=7.2 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.51 (m, 3H), 7.44 (m, 1H), 7.20 (m, 5H), 6.97 (m, 2H), 3.98 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[C:5]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([Cl:17])[CH:11]=1)([OH:9])[C:6]([OH:8])=[O:7].[CH2:22]1CCN2C(=NCCC2)CC1.CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[C:5]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([Cl:17])[CH:11]=1)([OH:9])[C:6]([O:8][CH3:22])=[O:7]
Reactant: O=C(O)C(O)(c1ccc(F)c(Cl)c1)c1ccc(F)c(Cl)c1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: CC#N
Product: COC(=O)C(O)(c1ccc(F)c(Cl)c1)c1ccc(F)c(Cl)c1

Procedure:
17.07 g (0.0512 mol) of 3,3′-dichloro-4,4′-difluorobenzilic acid, 14.10 g (0.0926 mol) of DBU, and 26.29 g (0.1852 mol) of methyl iodide are reacted in 200 ml acetonitrile analogously to step I.10.3. Yield: 6.77 g (38% of theory).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:23][CH2:24][CH:25]=O)[CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20]>>[CH2:1]([C:3]1[N:4]2[CH2:9][CH2:10][NH:11][CH:25]([CH2:24][CH2:23][C:15]3[CH:16]=[CH:17][C:18]([C:19]([F:20])([F:21])[F:22])=[C:13]([F:12])[CH:14]=3)[C:5]2=[C:6]([I:8])[N:7]=1)[CH3:2]
Reactant: O=CCCc1ccc(C(F)(F)F)c(F)c1
Reactant: CCc1nc(I)cn1CCN
Product: CCc1nc(I)c2n1CCNC2CCc1ccc(C(F)(F)F)c(F)c1

Procedure:
According to the general procedure (GP10), the microwave-assisted Pictet-Spengler reaction (60 W; 100° C.; 8 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (312.8 mg; 1.180 mmol) and 3-(3-fluoro-4-trifluoromethyl-phenyl)-propionaldehyde (260.4 mg; 1.180 mmol) afforded 3-ethyl-8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine which was Boc-protected and finally purified by HPLC.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[I:16][C:17]1[CH:22]=[C:21]([I:23])[CH:20]=[C:19]([I:24])[C:18]=1[OH:25].[OH-].[K+]>C(O)C>[I:16][C:17]1[CH:22]=[C:21]([I:23])[CH:20]=[C:19]([I:24])[C:18]=1[O:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: Oc1c(I)cc(I)cc1I
Reactant: O=C(O)CCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCCCCCCCCCOc1c(I)cc(I)cc1I
Reaction time: 12 h
Yield: 60.8 %

Procedure:
Ethanol (70 mL) was added with 12-bromododecanoic acid (4.8 g) and 2,4,6-triiodophenol (9.1 g) and the mixture was refluxed for dissolution. The solution was added with potassium hydroxide (2.2 g) and stirred for 12 hours. The precipitates obtained were separated by filtration, washed with ethanol and added with chloroform and 1 N hydrochloric acid to conduct extraction with chloroform twice. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed, and the resulting residue was purified by silica gel column chromatography to obtain 12-(2,4,6-triiodophenoxy)dodecanoic acid (7.0 g, yield: 60%). In the same manner as the synthetic method of 12-(2,4,6-triiodophenoxy)dodecanoic acid, 16-(2,4,6-triiodophenoxy)hexadecanoic acid was synthesized from 16-bromohexadecanoic acid.
Reaction SMILES: C[O-].[Na+].[C:4](OC(C)(C)C)(=O)C.C(O[C:15]([C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][O:23][C:20]2=[CH:21][N:22]=1)=[O:16])C.C(O)(=O)C.Cl>C1(C)C=CC=CC=1>[C:15]([C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][O:23][C:20]2=[CH:21][N:22]=1)(=[O:16])[CH3:4]
Reactant: CCOC(=O)c1cc2ccoc2cn1
Reactant: CC(=O)OC(C)(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2ccoc2cn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
As 405 mg (7.5 mmol) of sodium methoxide was stirred in 5 mL of toluene, 1.16 g (10.0 mmol) of tert-butyl acetate was added dropwise at room temperature to the solution. Then, 956 mg (5.0 mmol) of 5-ethoxycarbonylfuro[2,3-c]pyridine dissolved in 5 mL of toluene was added dropwise at room temperature to the above solution. After all the solution had been added, the reaction mixture was heated to 60° C., a reaction was carried out for 3 hours. The resulting reaction mixture was then neutralized with 450 mg (7.5 mmol) of acetic acid, the solution was stirred for 30 minutes, 1.5 mL (7.5 mmol) of 5 N hydrochloric acid was then added, and the solution was stirred for 5 hours at 60° C. to carry out a reaction. The solution was then returned to room temperature, the organic layer was separated, the aqueous layer was extracted twice with 5 mL of methylene chloride, and the combined organic layer was dried with anhydrous magnesium sulfate and then concentrated in a rotary evaporator. The resulting solids were recrystallized from a mixed solvent of toluene-hexane, giving 580 mg (72% yield) of 5-acetylfuro[2,3-c]pyridine in a purity of 99% by HPLC.
Reaction SMILES: [OH-].[Na+:2].C([O:5][C:6]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([O:15][CH3:16])[CH:9]=1)=[O:7])C>C1COCC1>[Na+:2].[CH3:16][O:15][C:10]1[CH:9]=[C:8]([C:6]([O-:7])=[O:5])[CH:13]=[C:12]([CH3:14])[N:11]=1
Reactant: CCOC(=O)c1cc(C)nc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)[O-])cc(C)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 6.1 ml portion of 1 N aqueous sodium hydroxide was added to 10 ml of THF containing 1.20 g of 2-methoxy-6-methyl-4-pyridinecarboxylic acid ethyl ester and stirred at room temperature for 1 hour and 20 minutes, and then the reaction solvent was evaporated to obtain 2-methoxy-6-methyl-4-pyridinecarboxylic acid sodium salt. Thereafter, the title compound was obtained by the same procedure of Example 18-1.
Reaction SMILES: B([C:4]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:5]=1[O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])(O)O.Br[C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[CH3:31][N:30]([CH3:32])[S:27]([C:24]1[CH:23]=[CH:22][C:21]([C:4]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:5]=2[O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:26][CH:25]=1)(=[O:28])=[O:29]
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1
Reactant: C[C@H](Oc1ccc(C(F)(F)F)cc1B(O)O)C(=O)O
Product: C[C@H](Oc1ccc(C(F)(F)F)cc1-c1ccc(S(=O)(=O)N(C)C)cc1)C(=O)O

Procedure:
The title compound was prepared by the method of example 144 step (i) using the product from example 146 step (iv) and 4-bromo-N,N-dimethyl-benzenesulfonamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:11]([CH:22]([CH3:24])[CH3:23])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:25]Br.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][C:9]1[C:13]([Br:25])=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[N:11]([CH:22]([CH3:24])[CH3:23])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: COc1ccc(-c2cc(OCc3ccccc3)nn2C(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2c(Br)c(OCc3ccccc3)nn2C(C)C)cc1
Reaction time: 1 h

Procedure:
To a solution of 3-benzyloxy-1-isopropyl-5-(4-methoxy-phenyl)-1H-pyrazole (3.7 g) in dichloromethane (50 mL) was added bromine (0.98 mL) at 0° C., and the mixture was stirred for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/dichloromethane=2/1) to give the title compound (3.3 g).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[O:13][CH3:14].S(=O)(=O)(O)O.[CH3:20]O>>[OH:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:20])=[O:9])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: CO
Reactant: COc1cc(C=CC(=O)O)ccc1O
Agent: O=S(=O)(O)O
Product: COC(=O)/C=C/c1ccc(O)c(OC)c1
Temperature: -25 °C

Procedure:
100 g of 4-hydroxy-3-methoxycinnamic acid were dissolved in 1 l of methanol and treated with 14.4 ml of concentrated sulphuric acid. The solution was heated under reflux for 2.5 hrs. Subsequently, the majority of the methanol (about 750 ml) was distilled off and the residue remaining was poured into 1 l of water. Then, the mixture was extracted three times with 500 ml of ethyl acetate each time and the organic phases were combined, washed twice with 250 ml of 10% sodium bicarbonate solution each time, dried over sodium sulphate, filtered and evaporated. The residue was dissolved in 800 ml of methanol, filtered and, for crystallization, cooled to -25° C. The crystals were thereupon filtered off under suction, washed with 100 ml of cold methanol and dried in a high vacuum at room temperature. This gave 54.7 g of yellowish colored crystals.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][NH:8][C:9](=[O:24])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([CH:21]=[O:22])[C:15]=2[F:23])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].[BH4-].[Na+]>CCO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:24])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([CH2:21][OH:22])[C:15]=2[F:23])[O:11][CH2:12][CH3:13])=[CH:25][CH:26]=1)#[N:2]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(CO)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.7 %

Procedure:
A suspension of (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-3-formyl-phenyl)-2-ethoxy-acetamide (300 mg) in EtOH (1 ml) was treated with NaBH4 (66 mg) at 0°. The reaction mixture was stirred for 4 hrs at rt, then poured onto ice and extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtrated and concentrated. The crude product was isolated by flash chromatography (CH2CH12=>CH2C2-12MeOH 4:1) to give (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-3-hydroxymethyl-phenyl)-2-ethoxy-acetamide (174 mg) as amourphous white solid. MS 361.3 ([M+H]+)
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH:9]=[CH:8][N:7]=2)=[N:4][N:3]=[N:2]1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]=[C:29]=[O:30])[CH:23]=1>>[NH:4]1[C:5]([C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:29]([NH:28][C:24]4[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:31])[F:32])[CH:23]=4)=[O:30])=[CH:17][CH:18]=3)[CH:9]=[CH:8][N:7]=2)=[N:1][N:2]=[N:3]1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2ccnc(-c3nnn[nH]3)c2)cc1
Product: O=C(Nc1ccc(Oc2ccnc(-c3nnn[nH]3)c2)cc1)Nc1cccc(C(F)(F)F)c1
Reaction time: 4 h

Procedure:
The title compound is prepared as described in Example 102 but using 4-[2-(1H-tetrazol-5-yl)-pyridin-4-yloxy]-phenylamine and α,α,α-trifluoro-m-tolyl-isocyanate. The reaction mixture is stirred for 4 h. The crude product Is washed with a solution of CH2Cl2/MeOH (95/5) and dried In vacuo to afford the title compound as a beige solid: ES-MS: 441.9 [M+H]+; single peak at tR=7.93 min (System 2); Rf=0.36 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [CH3:1][C@:2]([NH:24]C(=O)OC(C)(C)C)([C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([O:22][CH3:23])[CH:16]=2)=[CH:12][CH:13]=1)=[O:6])[CH2:3][CH3:4].C(O)(C(F)(F)F)=O>ClCCl>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:11]2[N:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C@:2]([CH3:1])([CH2:3][CH3:4])[NH2:24])=[CH:13][CH:12]=2)=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@](C)(N)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To a solution of 1,1-dimethylethyl ((1R)-1-methyl-1-{[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Intermediate 98, 65 mg) in dry dichloromethane (3 mL) cooled to 0° C., TFA (0.700 mL, 9.08 mmol) was added dropwise. The reaction was stirred at that temperature for 2 hours. The reaction was quenched with a saturated aqueous solution of NaHCO3 (20 mL) added at 0° C., and extracted with dichloromethane (3×7 mL). The combined organic layers were dried over sodium sulphate, filtered and evaporated to afford the title compound as a white solid (44 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:7])[CH2:4][CH2:5][SH:6].[CH2:8]([C:15]([N:33]([CH3:35])[CH3:34])([CH2:31][CH3:32])[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CN(C)C=O>[CH2:8]([C:15]([N:33]([CH3:35])[CH3:34])([CH2:31][CH3:32])[C:16]([C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([S:6][CH2:5][CH2:4][CH2:3][SH:7])=[CH:26][CH:25]=2)=[CH:22][CH:23]=1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(-c2ccc(Br)cc2)cc1)N(C)C
Reactant: SCCCS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(-c2ccc(SCCCS)cc2)cc1)N(C)C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
9.2 mmol of sodium hydride are suspended in 40 ml of dry dimethylformamide and 2.3 ml (23 mmol) of 1,3-propanedithiol are added dropwise. Then 2.0 g (4.6 mmol) of 2-benzyl-1-(4'-bromo-biphenyl-4-yl)-2-dimethylamino-butan-1-one (prepared by the method described in U.S. Pat. No. 5,534,629) in 60 ml of dimethylformamide are added dropwise. After stirring the solution at 100° C. for 2 h, the solution is poured into water. The crude product is extracted with methylene chloride, washed with water, dried over MgSO4, and concentrated. The residue is purified by column chromatography on silica gel with ethyl acetate-hexane (10:90) as an eluent. The structure of the product is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 0.72 (t, 3H), 1.37 (t, 1H), 1.84-2.01 (m, 3H), 2.09 (dq, 1H), 2.40 (s, 6H), 2.68 (dt, 2H), 3.10 (t, 2H), 3.23 (s, 2H), 7.15-7.29 (m, 5H), 7.41 (d, 2H), 7.55-7.62 (m, 4H), 8.41 (d, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[S:11][C:10]([CH2:12][CH3:13])=[N:9][N:5]2[C:6](=[O:8])[CH:7]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:12]([C:10]1[S:11][C:4]2=[N:3][C:2]([N:17]3[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]3)=[CH:7][C:6](=[O:8])[N:5]2[N:9]=1)[CH3:13]
Reactant: CCc1nn2c(=O)cc(Cl)nc2s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nn2c(=O)cc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2s1
Temperature: 150 °C

Procedure:
To a solution of 7-chloro-2-ethyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (2.0 g, 9.27 mmol, 1.0 equiv) in 50 mL of anhydrous acetonitrile in a microwave vial is added tert-butyl 1-piperazinecarboxylate (2.073 g, 11.13 mmol, 1.2 equiv) followed by N,N-diisopropylethylamine (4.86 mL, 27.8 mmol, 3.0 equiv). The mixture is heated in a microwave reactor for 25 min at 150° C. Upon completion, the mixture is concentrated in vacuo to give crude tert-butyl 4-(2-ethyl-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate as a yellow oil. This material is advanced directly to the next step.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:7](N)([NH2:10])(=[O:9])=[O:8]>O1CCOCC1>[N:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NS(N)(=O)=O
Reactant: C1CCNCC1
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCCCC1

Procedure:
Piperidine (3.0 g) and sulfamide (5.93 g) in 1,4-dioxane (100 ml) were heated at reflux for 24 h. The solvent was evaporated under reduced pressure and the resulting solid suspended in CHCl3. The suspension was filtered and the filtrate concentrated in vacuo to afford the subtitle compound as a white solid. Yield: 3.85 g.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH3:23][C@H:24]1[N:29]([CH3:30])[C@@H:28]([CH3:31])[CH2:27][N:26]([C:32]2[N:37]=[CH:36][C:35]([C:38](OC)=[O:39])=[CH:34][N:33]=2)[CH2:25]1.Cl>C1(C)C=CC=CC=1.CO>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:38]([C:35]3[CH:36]=[N:37][C:32]([N:26]4[CH2:27][C@H:28]([CH3:31])[N:29]([CH3:30])[C@H:24]([CH3:23])[CH2:25]4)=[N:33][CH:34]=3)=[O:39])[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1cnc(N2C[C@@H](C)N(C)[C@@H](C)C2)nc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4C[C@@H](C)N(C)[C@@H](C)C4)nc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 39.4 %

Procedure:
Trimethylaluminium (2M in toluene, 1.04 ml, 2.08 mmol) was added dropwise to a suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (205 mg, 0.83 mmol) and methyl 2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)pyrimidine-5-carboxylate (220 mg, 0.83 mmol) in toluene (5.257 ml) at 25° C. The resulting solution was stirred at 60° C. for 18 h. The reaction mixture was poured into methanol (50 mL) and acidified with HCl (2M aqueous solution, to obtain a clear freely stirring solution). The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The impure material was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (157 mg, 39%) as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=O)[CH2:14][CH2:15][N:16]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH3:17])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH3:17])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(NC(=O)CCN(C)CCc2ccc(OC)c(OC)c2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCOc1ccc(NCCCN(C)CCc2ccc(OC)c(OC)c2)cc1

Procedure:
In a manner similar to Preparation 2 react N-[4-butoxyphenyl]-3-[[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino]propionamide with lithium aluminum hydride to obtain the title compound.