Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5](=[O:23])[NH:6][C:7]1[CH:8]=[C:9]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[NH:13][C:10]2=[N:11][CH:12]=1)([CH3:3])[CH3:2].[C:24](Cl)(=[O:26])[CH3:25]>N1C=CC=CC=1>[CH:1]([O:4][C:5](=[O:23])[NH:6][C:7]1[CH:8]=[C:9]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:24](=[O:26])[CH3:25])[CH:17]=3)[NH:13][C:10]2=[N:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)Nc1cnc2[nH]c(-c3cccc(N)c3)nc2c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-c2nc3cc(NC(=O)OC(C)C)cnc3[nH]2)c1

Procedure:
10 mg of the product from example 5-1 were dissolved in 1 ml dry pyridine and 7 μl acetyl chloride were added at room temperature. After stirring over night, the solvent was evaporated and the residue dissolved in 3 ml methanol. 1 ml conc. ammonia were added and the mixture stirred for 1 hr at room temperature.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]([C:28]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[CH2:15][CH:16]=[CH:17][C:18]3[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([C:25](=[NH:27])[NH2:26])[CH:19]=3)=[CH:10][C:9]=2[C:35]([F:38])([F:37])[F:36])[CH2:3][CH2:2]1.[C:39](Cl)(=[O:41])[CH3:40].CCN(CC)CC.[Li+].[OH-]>CC#N.O>[C:39]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]([C:28]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[CH2:15][CH:16]=[CH:17][C:18]3[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([C:25](=[NH:26])[NH2:27])[CH:19]=3)=[CH:10][C:9]=2[C:35]([F:36])([F:37])[F:38])[CH2:3][CH2:2]1)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: N=C(N)c1ccc(O)c(C=CCN(C(=O)CCC(=O)O)c2ccc(OC3CCNCC3)c(C(F)(F)F)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(=O)N1CCC(Oc2ccc(N(CC=Cc3cc(C(=N)N)ccc3O)C(=O)CCC(=O)O)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine (400 mg) in 100 mL CH3CN was added acetyl chloride (500 mg) and Et3N (1.28 g) at ambient temperature. The resulting solution was stirred at ambient temperature for 2 hours. LiOH (500 mg) in water (1.0 mL) was then added to the reaction mixture and the resulting reaction mixture was stirred at ambient temperature for 2 hours. Acidification with trifluoroacetic acid, concentration, purification on HPLC (H2O/CH3CN, gradient) and freeze-drying afforded 4-(N′-(acetyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-hydroxy-3- amidinophenyl)prop-2-en-1-yl)benzenamine.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:17][C@H:18]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:44](Br)[CH:45]=[CH2:46]>CN(C)C=O.C(OCC)(=O)C>[CH2:46]([N:22]1[C@@H:19]2[C@H:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17][C@@:16]1([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C@H:15]([O:14][CH2:13][C:5]1[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:36])([F:1])[F:37])[CH:4]=1)[CH2:21][CH2:20]2)[CH:45]=[CH2:44]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)C[C@H]2C(=O)OC(C)(C)C

Procedure:
(1R*,2R*,5S*,6R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 25; 2.1 g, 4.0 mmol), potassium carbonate (1.7 g, 12.0 mmol) and allyl bromide (0.42 ml, 4.8 mmol) in dimethylformamide (10 ml) were stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate and washed with water. The organics were collected, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography, eluting with 10% ethyl acetate/iso-hexane, (1.8 g, 80%).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:20]=3[CH:30]=2)[C@@H:11]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][O:38][CH2:39][C@H:40]([O:42][CH2:43][CH3:44])[CH3:41])=[CH:33][CH:32]=2)[C@H:10]([CH:45]=O)[CH2:9]1)=O)(C)(C)C.[NH:47]1[CH2:51][CH2:50][CH2:49][CH2:48]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:43]([O:42][C@H:40]([CH3:41])[CH2:39][O:38][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([C@H:11]2[C@H:10]([CH2:45][N:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)[CH2:9][NH:8][CH2:13][C@@H:12]2[O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:20]=3[CH:30]=2)=[CH:32][CH:33]=1)[CH3:44]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2[C@H](C=O)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CN3CCCC3)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reaction time: 5 h

Procedure:
To a solution of 1 mmol of (3S,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-3-formyl-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester in 5 ml of THF are added 1.2 mmol of pyrrolidine, 1.1 mmol of acetic acid and 1.5 mmol of sodium triacetoxyborohydride. The reaction mixture is stirred for 5 h, and poured on an ice H2O mixture. The mixture is extracted with TBME (3×). The combined organic phases are washed with H2O and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound, which is identified based on the Rf value.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:14])[CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:2]1>CO.O.C1COCC1.[OH-].[Na+]>[O:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:14])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:2]1
Reactant: CCOC(=O)CCC(=O)c1ccoc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)c1ccoc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The keto ester from Step 1 (38.9 g, 0.193 mmoL) was dissolved in a mixture of MeOH:H2O:THF (3:1:2) (150 mL) and NaOH 1N (213 mL, 0.213 mmoL) was added. The reaction was stirred at r.t. overnight. The mixture was concentrated, acidified with HCl 1N extracted (2×) with EtOAc, washed with brine, dried over MgSO4, filtered and evaporated to afford the title product as a beige solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]=O.[N:10]1[N:11]2[CH:19]=[CH:18][CH:17]=[C:12]2[C:13]([NH2:16])=[N:14][CH:15]=1>C(O)(=O)C>[NH2:16][C:13]1[C:12]2=[CH:17][CH:18]=[C:19]([CH2:8][N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)[N:11]2[N:10]=[CH:15][N:14]=1
Reactant: C=O
Reactant: OC1CCNCC1
Reactant: Nc1ncnn2cccc12
Solvent: CC(=O)O
Product: Nc1ncnn2c(CN3CCC(O)CC3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Hydroxypiperidine (3.62 g, 35.8 mmol) and 37% formalin solution (2.9 g, 35.8 mmol) were dissolved in acetic acid (150 mL) and stirred at room temperature for 1 h. To this solution was added a solution of pyrrolo[2,1-f][1,2,4]triazin-4-amine (2.0 g, 14.9 mmol; prepared according to the procedure described in WO 2007/056170-A2, Intermediate A) in acetic acid (150 mL), and the mixture was stirred at 60° C. for 2 h. The solvent was then evaporated, and the residue was taken up in 200 mL of half-concentrated aqueous potassium bicarbonate solution and extracted with 200 mL dichloromethane. The organic layer was washed with water (2×50 mL) and discarded. The combined aqueous layers were evaporated to dryness, and the residue was treated with a 10:1 mixture of dichloromethane and methanol (2×100 mL). The organic extracts were evaporated, and the residue was purified by preparative HPLC (method 4) to give 1.16 g (15% of th.) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)#[N:2].CCN(C(C)C)C(C)C.CN(C([O:28]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:46][C:47]1[C:48]([C@H:53]([C:55]2[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=2)[NH2:54])=[N:49][CH:50]=[CH:51][CH:52]=1.Cl.FC(F)(F)C1C=CC([C@@H](C2C(C(F)(F)F)=CC=CN=2)N)=CC=1>C(Cl)Cl.O>[F:46][C:47]1[C:48]([C@H:53]([C:55]2[CH:60]=[CH:59][C:58]([C:61]([F:63])([F:64])[F:62])=[CH:57][CH:56]=2)[NH:54][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]([NH2:2])=[O:28])=[CH:8][N:7]=2)=[O:11])=[N:49][CH:50]=[CH:51][CH:52]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=O)c1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2F)nc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-cyanopicolinic acid (93 mg, 0.628 mmol) in DCM (6 mL) were added DIPEA (0.3 mL, 1.722 mmol) and HATU (247 mg, 0.650 mmol). The solution was stirred at rt. After 20 minutes, the reaction was treated with (S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine hydrochloride (Intermediate 2) (115 mg, 0.426 mmol). After stirring for 16 h, the reaction was poured into H2O (20 mL). The aqueous layer was back-extracted with DCM (10 mL). The combined DCM layers were concentrated in vacuo and taken up in 3 mL of concentrated sulfuric acid. The mixture was stirred at rt for 4 hours and then was poured into 75 g of ice. After stirring for 1 hour, the reaction was filtered, and the solids were rinsed with H2O. The solids were then taken up in EtOAc (30 mL) and washed with saturated aqueous NaHCO3. The EtOAc layer was concentrated in vacuo to give the title compound as an off-white solid. 1H NMR (CDCl3, 300 MHz) δ ppm 9.93 (d, J=7.5 Hz, 1H), 9.07 (s, 1H), 8.53 (d, J=4.7 Hz, 1H), 8.23-8.27 (m, 2H), 7.61 (d, J=8.3 Hz, 2H), 7.55 (d, J=8.3 Hz, 2H), 7.42 (td, J=8.2, 1.3 Hz, 1H), 7.27-7.35 (m, 1H), 6.69 (dd, J=7.8, 1.9 Hz, 1H), 5.92 (br s, 2H). MS (ESI pos. ion) m/z: 419.9 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:9]([NH2:10])=[CH:8][CH:7]=[C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([F:20])([F:19])[F:18])[CH2:12]2)[C:3]=1[C:4]#[N:5].[Cl:21][C:22]1[CH:38]=[CH:37][C:25]([CH2:26][NH:27][C:28]([C:30]2([C:33]([F:36])([F:35])[F:34])[CH2:32][CH2:31]2)=[O:29])=[CH:24][C:23]=1[N:39]=[C:40]=S.C(Cl)CCl>CN(C=O)C>[Cl:21][C:22]1[CH:38]=[CH:37][C:25]([CH2:26][NH:27][C:28]([C:30]2([C:33]([F:36])([F:35])[F:34])[CH2:31][CH2:32]2)=[O:29])=[CH:24][C:23]=1[NH:39][C:40]1[NH:10][C:9]2[CH:8]=[CH:7][C:6]([N:11]3[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([F:20])([F:18])[F:19])[CH2:12]3)=[C:3]([C:4]#[N:5])[C:2]=2[N:1]=1
Reactant: N#Cc1c(N2CCCC(C(F)(F)F)C2)ccc(N)c1N
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: N#Cc1c(N2CCCC(C(F)(F)F)C2)ccc2[nH]c(Nc3cc(CNC(=O)C4(C(F)(F)F)CC4)ccc3Cl)nc12

Procedure:
The title compound was prepared in analogy to Example 71 using 2,3-diamino-6-(3-trifluoromethyl-piperidin-1-yl)benzonitrile (115 mg, 0.40 mmol), N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (135 mg; 0.40 mmol), EDC (77 mg, 0.40 mmol) and DMF (3 mL).
Reaction SMILES: [F:1][C:2]([F:6])([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>ClCCl>[F:1][C:2]([F:6])([CH3:5])[CH2:3][O:4][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(F)(F)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC(C)(F)F)cc1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To a solution of 2,2-difluoropropanol (0.50 g, 5.20 mmol) in dichloromethane (52.0 mL) and triethylamine (0.50 g, 0.73 mL, 5.20 mmol) at 0° C. is added p-toluenesulfonyl chloride (0.99 g, 5.20 mmol). The mixture is allowed to slowly warm to room temperature over 24 h. The mixture is concentrated and is partitioned between diethyl ether and water. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to dryness. The material is purified over silica gel to obtain 1.0 g of the title compound as clear crystals. MS (m/z) 250 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[S:10]([N:13]=C=O)(=[O:12])=[O:11].C1C=CC=CC=1>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]([O:8][S:10](=[O:12])(=[O:11])[NH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1cccc(I)c1
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: NS(=O)(=O)Oc1cccc(I)c1
Yield: 78 %

Procedure:
This compound was prepared using the procedure of Example 84 from 27.8 g (0.126 mole) of 3-iodophenol and 11.7 ml (0.135 mole) of chlorosulfonyl isocyanate in 100 ml of toluene to obtain 29.4 g (78%) of the title compound as white flakes, mp 106°-108° C. (benzene).
Reaction SMILES: Br[C:2]1[O:23][C:5]2[N:6]([CH3:22])[CH:7]=[C:8]([C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:12])[C:9](=[O:10])[C:4]=2[CH:3]=1.[CH2:24]([OH:28])[CH2:25][C:26]#[CH:27]>C(N(CC)CC)C.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:11]([C:8]2[C:9](=[O:10])[C:4]3[CH:3]=[C:2]([C:27]#[C:26][CH2:25][CH2:24][OH:28])[O:23][C:5]=3[N:6]([CH3:22])[CH:7]=2)=[O:12])=[CH:16][CH:17]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(Br)oc21
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCCO)oc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-N-(4-chlorobenzyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]-pyridine-5-carboxamide (Example 79, 0.100 g) was suspended in a mixture of triethylamine (2.5 mL) and DMF (0.5 mL). CuI (0.006 g), Pd(PPh3)2Cl2 (0.017 g), and then 3-butyn-1-ol (0.038 mL) were added. The mixture was stirred at room temperature for 30 min and then was partitioned between CH2Cl2 (10 mL) and water (10 mL). The aqueous layer was separated and was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with a sat. aq. ammonium chloride solution (10 mL), dried (MgSO4), filtered, and concentrated in vacuo. The resulting solid was purified by column chromatography (CH2Cl2/methanol; 99/1, 98/2) followed by recrystallization from ethyl acetate to yield 0.035 g of the title compound as a pale yellow solid. Physical characteristics. M.p. 242-243° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 10.51, 8.59, 7.41-7.32, 7.21, 5.01, 4.55, 3.92, 3.61, 2.67; MS (ESI+) m/z 385 (,M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:8]([NH2:16])=[CH:9][C:10]3[O:14][CH2:13][O:12][C:11]=3[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[K+].[C:18]([C:20]1[N:21]=[C:22]([C:33]([O-])=[O:34])[N:23](COCC[Si](C)(C)C)[CH:24]=1)#[N:19]>>[C:1]1([C:7]2[C:8]([NH:16][C:33]([C:22]3[NH:21][C:20]([C:18]#[N:19])=[CH:24][N:23]=3)=[O:34])=[CH:9][C:10]3[O:14][CH2:13][O:12][C:11]=3[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: Nc1cc2c(cc1C1=CCCCC1)OCO2
Agent: [K+]
Product: N#Cc1cnc(C(=O)Nc2cc3c(cc2C2=CCCCC2)OCO3)[nH]1

Procedure:
The title compound was prepared by coupling 6-cyclohex-1-enyl-benzo[1,3]dioxol-5-ylamine (prepared in the previous step) and 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (prepared in Example 11, step (d)) according to the procedure in Example 42, step (c) followed by SEM deprotection according to the procedure in Example 11, step (g). 1H-NMR (DMSO-d6, 400 MHz): δ 14.23 (s, 1H), 9.67 (s, 1H), 8.31 (s, 1H), 7.48 (s, 1H), 6.78 (s, 1H), 6.01 (s, 2H), 5.69 (s, 1H), 2.20-2.05 (m, 4H), 1.71-1.57 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C18H16N4O3, 337.1 (M+H), found 337.0.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][OH:47])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][OH:47])[CH:42]=[CH:43][N:44]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCO)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCO)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-(2-hydroxyethyl)-1H-imidazol-2-yl]methyl]thio]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.40 g) in dichloromethane (10 ml) was added a solution of 3-chloroperbenzoic acid (70%, 0.22 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., an aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with an aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethanol:ethyl acetate 1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-(2-hydroxyethyl)-1H-imidazol-2-yl]methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 434) (280.5 mg) as yellow amorphous.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[H-].[Na+].Br[CH2:15][C:16]([CH3:23])=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH-].[Na+]>CN(C=O)C.CCOCC>[CH3:15][C:16]([CH2:23][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCOC(=O)C=C(C)CBr
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C=C(C)COc1ccc(C=O)cc1OC
Reaction time: 0.17 h

Procedure:
Vanillin (3.43 g, 22.5 mmol) in 10 ml of DMF is added portionwise, at 0°, to sodium hydride (21.5 g, 23.6 mmol) in ml of DMF. The mixture is stirred for 10 min. and then ethyl 4-bromo-3-methyl-2-butenoate (4.87 g, 23.5 mmol) in 3 ml of DMF is added. After 3 hours, the reaction mixture is poured into ether and 5% sodium hydroxide solution. The aqueous layer is extracted with ether, and the organic layers are combined and washed with 5% sodium hydroxide, with water and with brine and dried. Solvent is removed in vacuo and the crude product is chromatographed to give ethyl 3-methyl-4-(4-formyl-2-methoxyphenoxy)-2-butenoate. To isopropyltriphenylphosphonium iodide (2.26 g, 5.23 mmol) in 15 ml of tetrahydrofuran (THF) is added n-butyllithium (1.6 M; 3.10 ml, 5.0 mmol) at -5°. The mixture is cooled to -60°, and ethyl 3-methyl-4-(4-formyl-2-methoxyphenoxy)-2-butenoate (0.70 g, 2.51 mmol) in 10 ml of THF is added. After 45 min. the reaction mixture is poured into ether and water, and the aqueous phase is extracted with ether. The combined ether layers are washed with water and with brine and dried. Solvent is removed in vacuo, and the crude product is triturated with hexane and the hexane-soluble fraction is purified by prep. TLC to give ethyl 3-methyl-4-[2-methoxy-4-(2-methyl-1-propenyl)phenoxy]-2-butenoate, MS m/e 304 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([C:12]1[CH:17]=[CH:16][C:15](SC)=[CH:14][CH:13]=1)=[CH:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:2].O[O:22][S:23]([O-:25])=O.[K+].[CH3:27]O>>[CH2:1]([O:3][C:4](=[O:20])/[C:5](/[C:12]1[CH:13]=[CH:14][C:15]([S:23]([CH3:27])(=[O:25])=[O:22])=[CH:16][CH:17]=1)=[CH:6]/[CH2:7][CH2:8][CH:9]([CH3:10])[CH3:11])[CH3:2]
Reactant: O=S([O-])OO
Reactant: CO
Reactant: CCOC(=O)C(=CCCC(C)C)c1ccc(SC)cc1
Agent: [K+]
Product: CCOC(=O)/C(=C/CCC(C)C)c1ccc(S(C)(=O)=O)cc1

Procedure:
Following the method of example 54d, oxidation of 6-methyl-2-(4-methylsulfanyl-phenyl)-hept-2-enoic acid ethyl ester (320 mg, 1.09 mmol) with oxone® (0.87 mg, 1.4 mmol) in methanol gives the title compound as a yellow oil (327 mg). MS (m/e): 325 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][OH:29])=[CH:22][CH:21]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.C(N(C(C)C)CC)(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:40][S:41]([O:29][CH2:28][CH2:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][N:14]2[CH2:13][C@@H:12]([C:10]3[CH:9]=[CH:8][C:6]4[O:7][C:2]([CH3:30])([CH3:1])[O:3][CH2:4][C:5]=4[CH:11]=3)[O:16][C:15]2=[O:17])=[CH:25][CH:24]=1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCO)cc4)C(=O)O3)ccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOS(C)(=O)=O)cc4)C(=O)O3)ccc2O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-{2-[4-(2-hydroxyethoxy)phenyl]ethyl}-1,3-oxazolidin-2-one (450 mg) in DCM (20 ml) at 0° C. under nitrogen was treated with diisopropylethylamine (0.23 ml) followed by methanesulphonyl chloride (0.09 ml) and the mixture was stirred at 0° C. for 1 h. Saturated NaHCO3 solution was added and the mixture was vigorously stirred for 5 min. The layers were separated and the organic phase washed with saturated NaHCO3 solution, dried (Na2SO4) and the solvent evaporated in vacuo to give the title compound (528 mg). LCMS RT=3.15 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[CH2:11]([NH:13][CH2:14][CH:15]=[O:16])[CH3:12]>C1C=CC=CC=1>[CH2:11]([N:13]([CH2:14][CH:15]=[O:16])[C:9]([NH:8][C:6]1[S:7][C:3]([O:2][CH3:1])=[N:4][N:5]=1)=[O:10])[CH3:12]
Reactant: COc1nnc(N=C=O)s1
Reactant: CCNCC=O
Solvent: c1ccccc1
Product: CCN(CC=O)C(=O)Nc1nnc(OC)s1

Procedure:
A mixture of 5-methoxy-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-ethylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-ethyl-3-(5-methoxy-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)[NH:10][C:9]=2[C:8]([OH:22])=[CH:7][CH:6]=1)=[O:4].O[Li].O>C1COCC1.CO.O>[Cl:21][C:16]1[CH:15]=[C:14]([C:11]2[NH:10][C:9]3[C:8]([OH:22])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=2)[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: COC(=O)c1ccc(O)c2[nH]c(-c3ccc(F)c(Cl)c3)nc12
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(F)c(Cl)c3)nc12
Temperature: 25 °C
Yield: 89.4 %

Procedure:
Wang resin-supported 2-(3-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester (570 mg, 0.47 mmol) obtained in step 5 was dissolved in THF, LiOH.H2O (99 mg, 2.35 mmol) in MeOH—H2O was added thereto and the resulting mixture was refluxed for 5 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with MeOH and CH2Cl2, and dried to obtain the title compound (551 mg, 0.42 mmol) in a yield of 90%.