Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14]C)=O)[CH:5]=[C:6](Br)[N:7]=1.[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([N:31](CC)[CH:32]([CH3:34])[CH3:33])(C)C.C1CC=CCC=1>[Pd].O1CCCC1>[CH:32]1([NH:31][C:12](=[O:14])[C:11]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:9]([N:4]3[CH:5]=[CH:6][N:7]=[C:2]([O:27][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:3]3=[O:20])[CH:10]=2)[CH2:34][CH2:33]1
Reactant: Oc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(Br)c2=O)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: C1=CCC=CC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(Oc2ccccc2)c1=O
Temperature: 140 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1b, 204 mg), phenol (206 mg), N,N-diisopropylethylamine (0.3 mL) and tetrahydrofuran (1 mL) was heated within a microwave for 60 minutes at 140° C. before being cooled to room temperature. The mixture was transferred to a mixture of palladium on carbon (10%, 38 mg) and tetrahydrofuran (1 mL). 1,4-Cyclohexadiene (1 mL) was added and the mixture was heated under atmosphere of nitrogen within a microwave for 10 minutes at 90° C. before being cooled to room temperature. The mixture was filtered and concentrated. The residue was treated with tetrahydrofuran (10 mL), water (2 mL) and lithium hydroxide (193 mg). The mixture was stirred for 2 h, diluted with ethyl acetate, washed with 2M hydrochloric acid and water. The organic phase was dried (Na2SO4) and concentrated. The solid was washed with small amount of diethyl ether and treated with dichloromethane (3 mL) then N,N-dimethylformamide (1 drop) and oxalyl chloride (0.05 mL) were added. The mixture was stirred till solid disappeared and the solution of acid chloride was transferred to a solution of cyclopropylamine (0.3 mL) in dichloromethane (5 mL). The resulting mixture was stirred for 30 min. then diluted with ethyl acetate (50 mL). The mixture was washed with 2M hydrochloric acid and twice with water. The organic phase was dried (Na2SO4) and concentrated in vacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent) afforded the title compound as a solid (70 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[CH2:11]([N:8]1[CH2:9][CH2:10][C:6]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:4]([OH:5])=[O:3])[CH2:7]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCN(Cc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1(Cc2ccccc2)CCN(Cc2ccccc2)C1
Yield: 76.8 %

Procedure:
To a solution of 1,3-dibenzylpyrrolidine-3-carboxylic acid ethyl ester (Example A18e, 13.1 g, 41 mmol) in 250 mL of methanol is added 2N NaOH (46 mL, 92 mmol) and the reaction is heated to reflux for 24 hours. The solution is cooled, concentrated, redissolved in water and extracted with ether. The pH of the aqueous layer is adjusted to 7 and the precipitated solid is collected, to give 9.3 g of the title compound, MS EI+: m/z 296 (MH+), mp 209-210° C.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:10]=1[NH2:11].[Cl:17][CH2:18][C:19](Cl)=[O:20]>O1CCCC1>[Cl:17][CH2:18][C:19]([NH:11][C:10]1[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=1[OH:8])=[O:20]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(N)c(O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)CCl)c(O)c1
Temperature: 26 °C
Yield: 73.6 %

Procedure:
95 ml of triethylamine (0.674 mol) were added to a solution of 83 g of 2-hydroxy-4-methylaniline (0.674 mol) in 2.5 liters of tetrahydrofuran, with stirring and under an inert atmosphere, followed, after 30 minutes, by dropwise addition of a solution of 54 ml of chloroacetyl chloride (0.678 mol) in 60 ml of tetrahydrofuran, while maintaining the temperature at 25-27° C. The reaction medium was stirred at room temperature for 4 hours, filtered through a sinter funnel and the inorganic salts were rinsed with 500 ml of tetrahydrofuran. The combined organic phases were poured into 3 liters of ice-cold water with stirring. The precipitate formed was spin-filtered, washed with twice 600 ml of water and once with pentane, and dried under vacuum to constant weight, to give 99 g of 2-chloro-N-(2-hydroxy-4-methylphenyl)acetamide in the form of a beige-coloured powder, in a yield of 74%.
Reaction SMILES: [CH3:1][O:2][K].[CH:4]1[CH:9]=[C:8](Cl)[CH:7]=[C:6]([C:11]([O:13]O)=O)[CH:5]=1.O=P(Cl)(Cl)Cl.B(Br)(Br)Br.C=O.CN1C(=O)[N:31]([CH3:34])[CH2:30][CH2:29]C1>C(Cl)Cl.ClCCCl.OS(O)(=O)=O>[O:13]1[C:11]2[C:6]3[CH:5]=[CH:4][CH:9]=[CH:8][C:7]=3[CH:34]=[N:31][C:30]=2[CH2:29][O:2][CH2:1]1
Reactant: CO[K]
Reactant: CN1CCCN(C)C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: BrB(Br)Br
Agent: C=O
Agent: O=S(=O)(O)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: c1ccc2c3c(ncc2c1)COCO3

Procedure:
Reaction Conditions: (1) MeOK in DMPU; (2) MCPBA in CH2Cl2; (3) POCl3 in DCE; (4) BBr3 in CH2Cl2; (5) HCHO solution in 40% H2SO4 by procedure of Synthesis of 1,3-oxazino[5,6-c]isoquinolines and related compounds. Miyoko Toyama and Hirotaka Otomasu, Chem. Pharm. Bull. 33(12), 5543-5546, 1985; (6) Fluororination procedure by Uchibori, Y.; Umeno, M.; Yoshiokai, H.; Heterocycles, 1992, 34 (8), 1507-1510
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:20])[CH2:18][Cl:19])[O:4][N:3]=1.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>O1CCOCC1>[ClH:19].[CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:20])[CH2:18][NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])[O:4][N:3]=1
Reactant: Cc1cc(C=Cc2ccccc2OCC(O)CCl)on1
Reactant: CC(C)(C)N
Solvent: C1COCCO1
Product: Cc1cc(C=Cc2ccccc2OCC(O)CNC(C)(C)C)on1
Product: Cl

Procedure:
2.4 g of 3-methyl-5-[2-(2-hydroxy-3-chloropropoxy)-styryl]-isoxazole, 10 ml of tert.-butylamine and 50 ml of dioxane are heated for 10 hours at 100° C. in an autoclave. After distilling off the volatile constituents under reduced pressure, the very viscous crude product is partitioned between ether and 2 N sulfuric acid and the aqueous phase is cautiously rendered alkaline with 4 N sodium hydroxide solution and is finally extracted with ether. After drying the organic phase over sodium sulfate, the solvent is removed and the residue left is converted to 3-methyl-5-[2-(2-hydroxy-3-tert.-butylaminopropoxy)-styryl]-isoxazole hydrochloride, of melting point 216°-218° C., by the method described in Example 3.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f3) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1F.[OH:10][CH:11]([CH2:23][CH2:24][CH3:25])[CH2:12][CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]>>[CH3:19][C:17]([O:16][C:15](=[O:21])[N:14]([CH2:13][CH2:12][CH:11]([O:10][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1])[CH2:23][CH2:24][CH3:25])[CH3:22])([CH3:18])[CH3:20]
Reactant: CCCC(O)CCN(C)C(=O)OC(C)(C)C
Reactant: Fc1cc(Cl)ccc1Cl
Product: CCCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared according to the method of Example 3 step (b) but using 2,5-dichlorofluorobenzene and (3-hydroxyhexyl)methylcarbamic acid, 1,1-dimethylethyl ester.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5](#[N:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Cl-].[Zn+2].[Cl-]>[C:6]1([C:5]2[NH:12][N:3]=[N:2][N:1]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Product: c1ccc(-c2nnn[nH]2)cc1

Procedure:
As outlined in Scheme 8, benzonitrile is treated with sodium azide and zinc chloride to give 5-phenyltetrazole 14 which is converted to the N-trityl derivative 15 by treatment with triphenylmethyl chloride and triethylamine. The zinc reagent 16 was prepared by treatment with n-butyllithium followed by zinc chloride. Coupling with 4-iodotoluene using the catalyst bis(triphenylphosphine)nickel(II) dichloride gives the biphenyl product 17 in high yield. Treatment with N-bromosuccinimide in refluxing carbon tetrachloride, in the presence of a radical initiator such as benzoyl peroxide or 2,2'-azobisisobutyronitrile (AIBN), gives bromide 18.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]=[N:10][C:11]1[S:12][C:13]([S:29][CH3:30])=[C:14]([C:16]2[N:17]=[C:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=3)[S:19][CH:20]=2)[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=[O:32].[Cs+].[Cs+].Br[CH2:38][C:39]([NH2:41])=[O:40]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]=[N:10][C:11]1[S:12][C:13]([S:29][CH3:30])=[C:14]([C:16]2[N:17]=[C:18]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([O:32][CH2:38][C:39](=[O:40])[NH2:41])[CH:27]=3)[S:19][CH:20]=2)[CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1sc(N=CNC(=O)OC(C)(C)C)cc1-c1csc(Nc2ccc(O)cc2)n1
Reactant: O=C([O-])[O-]
Reactant: NC(=O)CBr
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSc1sc(N=CNC(=O)OC(C)(C)C)cc1-c1csc(Nc2cccc(OCC(N)=O)c2)n1
Temperature: 58 °C
Reaction time: 24 h
Yield: 12.4 %

Procedure:
To stirring solution of (tert-butoxy)-N-[(4-{2-[(4-hydroxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthio(2-thienyl))iminomethyl]carboxamide (65 mg, 0.14 mmol) in 1.5 mL of DMF was added sequentially Cs2CO3 (1.5 equiv, 60.1 mg, Aldrich Chemicals, Milwaukee, Wis.), bromoacetamide (1.2 equiv, 20.4 mg, Aldrich Chemicals, Milwaukee, Wis.), and a catalytic amount of KI. The reaction was warmed to 58° C. in an oil bath, stirred for 48 h, at which time another 0.6 equiv of bromoacetamide was added. Stirring was continued for another 24 h, at which time the reaction was filtered and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (50% ethyl acetate-hexanes) to give 9 mg (12% yield) of (tert-butoxy)-N-{[4-(2-{[3-(carbamoylmethoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthio(2-thienyl)]iminomethyl}carboxamide. Mass Spectrum (ESI) m/z calcd. for C22H25N5O4S3, 519.7 (M+H), found 519.7, 420.7 [—C(O)OC(CH3)3].
Reaction SMILES: C(N(CC)[CH2:4][CH2:5][C:6](=[O:19])[CH2:7][CH:8]([CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)C.CC(CC1C=CC=C(OC)C=1)CC(=O)C=C.[CH2:38]([CH:40]1[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46])[CH3:39]>[OH-].[K+]>[CH2:38]([C:40]1([CH2:4][CH2:5][C:6](=[O:19])[CH2:7][CH:8]([CH3:18])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46])[CH3:39]
Reactant: CCC1C(=O)CCC1=O
Reactant: CCN(CC)CCC(=O)CC(C)Cc1cccc(OC)c1
Agent: C=CC(=O)CC(C)Cc1cccc(OC)c1
Agent: [K+]
Agent: [OH-]
Product: CCC1(CCC(=O)CC(C)Cc2cccc(OC)c2)C(=O)CCC1=O

Procedure:
Add a mixture of 1-diethylamino-6-(m-methoxyphenyl)-5-methylhexan-3-one and 5-methyl-6-(m-methoxyphenyl)hex-1-en-3-one (6 g, prepared by slow distillation of the former substance) to 2-ethylcyclopentane-1,3-dione (3.5 g) in 0.12% methanolic potassium hydroxide (10 cc) and heat the mixture under reflux for 16 hours. Remove most of the solvent under reduced pressure and add ether (25 cc) and benzene (25 cc) to the residue. Wash the solution with 5% aqueous sodium hydroxide, water, dilute hydrochloric acid, and brine, and dry. Evaporate the solvent to obtain a viscous brown gum, which is the triketone 2-ethyl-2-(6-m-methoxyphenyl-5-methyl-3-oxohexyl)cyclopentane-1,3-dione.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([Cl:20])[C:18]#[CH:19]>C(#N)C>[ClH:20].[CH2:19]([NH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)[C:18]#[CH:17]
Reactant: C#CCCl
Reactant: NC1CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCNC1CCc2ccccc21
Product: Cl
Temperature: 60 °C

Procedure:
10.0 g of racemic 1-aminoindan and 10.4 g of potassium carbonate were added to 75 ml of acetonitrile. The resulting suspension was heated to 60° C. and 4.5 g of propargyl chloride was added dropwise.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][C:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>CN1C(=O)CCC1>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:2]2[CH:7]=[C:6]([N:8]3[CH:12]=[N:11][C:10]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:9]3)[CH:5]=[CH:4][N:3]=2)=[CH:24][CH:23]=1
Reactant: Clc1cc(-n2cnc(Nc3ccccc3)n2)ccn1
Reactant: COc1ccc(CN)cc1
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2cc(-n3cnc(Nc4ccccc4)n3)ccn2)cc1
Reaction time: 1 h

Procedure:
[1 g, 3.68 mMol] of [1-(2-Chloro-pyridin-4-yl)-1H-[1,2,4]triazol-3-yl]-phenyl-amine was dissolved in 14 mL of NMP with [2.4 mL, 2.52 g, 18.4 mMol] of p-methoxybenzylamine and heated 250 C for 15 min (MW, 150 W). The solvent was removed in vacuo (Kugel-Rohr style) and the residue was treated with MTBE. The ether was decanted away from the dark residue and was replaced with fresh MTBE and mass broken up with vigorous stirring. The ether was again decanted away and replaced with methanol and vigorously stirred for 1 hour. The tan solid was isolated via suction filtration and washed sequentially with methanol and MTBE. The resulting powder was boiled in hot acetonitrile for several minutes, allowed to cool, isolated via suction filtration, and washed with more acetonitrile and finally MTBE. Yield: 0.5 g (38.5%). 1H NMR 500 MHz (DMSO-d6) ∂ 3.7 (s, 3H), 4.45 (d, 2H), 6.85 (m, 3H), 6.93 (s, 1H), 6.98 (d, 1H), 0.3 (m, 5H), 7.64 (d, 2H), 8.05 (d, 1H), 9.1 (s, 1H), 9.5 (s ex, H). LC/MS [M+H+]=373.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1)[CH:7]=[CH:6]2.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.ClCCl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[C:8]([C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2c(O)c(-c3ccc(SC)cc3)ccc2c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3)c(-c3ccc(SC)cc3)ccc2c1
Yield: 78.2 %

Procedure:
Stir a solution of 6-methoxy-2-(4-methylsulfanyl-phenyl)-naphthalen-1-ol (1.98 g, 6.68 mmol), 4-fluoro-nitrobenzene (0.78 mL, 7.34 mmol) and phosphazene base P4-t-butyl (6.7 mL of 1M in hexane, 6.7 mmol) in N,N-dimethylformamide (30 mL) at ambient temperature for 4 hours. Dilute the reaction with dichloromethane, wash with 1N aqueous hydrochloric acid, water, dry with solid magnesium sulfate and chromatograph on silica gel with hexane/ethyl acetate mixtures to give 2.18 g of 6-methoxy-2-(4-methylsulfanyl-phenyl)-1-(4-nitro-phenoxy)-naphthalene (78%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][N:21]([CH3:32])[C:22]1[S:23][C:24]2[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][N:21]([CH3:32])[C:22]1[S:23][C:24]2[CH:30]=[C:29]([NH:31][C:8]([C:6]3[CH:5]=[CH:4][C:3]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[C:2]([CH3:1])[CH:7]=3)=[O:10])[CH:28]=[CH:27][C:25]=2[N:26]=1
Reactant: Cc1cc(C(=O)O)ccc1-c1ccccc1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Product: Cc1cc(C(=O)Nc2ccc3nc(N(C)CCN(C)C)sc3c2)ccc1-c1ccccc1

Procedure:
The title compound is prepared by following General Method A, using 2-methyl-biphenyl-4-carboxylic acid (0.072 g, 0.34 mmol), and N*2*-(2-dimethylamino-ethyl)-N*2*-methyl-benzothiazole-2,6-diamine (0.065 g, 0.26 mmol) to give 0.036 g, (31%) of product. LC/MS: Retention time=4.80 min; (m/z): calcd for C2H28N4OS (M+H)+: 445.6; found: 445.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[Mg].[Cl-].[Ce+3].[Cl-].[Cl-].[CH2:15]([N:22]1[CH2:30][C:29]2([C:31]([O:33][CH3:34])=[O:32])[CH:24]([C:25](=[O:41])[CH2:26][CH2:27][CH:28]2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)C>[CH2:15]([N:22]1[CH2:30][C:29]2([C:31]([O:33][CH3:34])=[O:32])[CH:24]([C:25]([OH:41])([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=3)[CH2:26][CH2:27][CH:28]2[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2c1ccccc1
Reactant: COc1cccc(Br)c1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(O)(c1cccc(OC)c1)CCC2c1ccccc1
Yield: 48.5 %

Procedure:
By carrying out the reaction as in Stage A of Example 6, but from 1.56 cm3 (12.4 mmol) of 3-bromoanisole and from 302 mg (12.4 mmol) of magnesium turnings at reflux for one hour in 5 cm3 of dry diethyl ether, followed successively by 1.02 g (4.13 mmol) of anhydrous cerium chloride and by a solution of 1.5 g (4.13 mmol) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate, obtained in Stage B of Example 1, in 8 cm3 of diethyl ether, 945 mg (48%) of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-(3-methoxyphenyl)-4-phenyloctahydroisoindole-3a-carboxylate were obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with cyclohexane and then with a cyclohexane/ethyl acetate (80/20 by volume) mixture, in the form of a white solid, the characteristic of which was as follows:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:4]([N:6]1[CH2:10][C@H:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=2)[CH2:8][C@H:7]1[C:19]([NH:21][C@H:22]([CH:28]([OH:35])[C:29]([NH:31][CH:32]1[CH2:34][CH2:33]1)=[O:30])[CH2:23][CH:24]1[CH2:27][CH2:26][CH2:25]1)=[O:20])=[O:5].C(N(CC)CC)C.[C:47]([N:51]=[C:52]=[O:53])([CH3:50])([CH3:49])[CH3:48]>ClCCl>[C:47]([NH:51][C:52](=[O:53])[NH:2][C@@H:3]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:4]([N:6]1[CH2:10][C@H:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=2)[CH2:8][C@H:7]1[C:19]([NH:21][C@H:22]([CH:28]([OH:35])[C:29]([NH:31][CH:32]1[CH2:33][CH2:34]1)=[O:30])[CH2:23][CH:24]1[CH2:27][CH2:26][CH2:25]1)=[O:20])=[O:5])([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)[C@H](N)C(=O)N1C[C@H](Oc2ccc(Cl)cn2)C[C@H]1C(=O)N[C@@H](CC1CCC1)C(O)C(=O)NC1CC1
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N[C@H](C(=O)N1C[C@H](Oc2ccc(Cl)cn2)C[C@H]1C(=O)N[C@@H](CC1CCC1)C(O)C(=O)NC1CC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-(5-chloro-pyridin-2-yloxy)-N-((2S)-1-cyclobutyl-4-(cyclopropylamino)-3-hydroxy-4-oxobutan-2-yl)pyrrolidine-2-carboxamide HCl salt (45 mg, 0.077 mmol) in dichloromethane (3.0 mL) was added triethylamine (0.02 mL, 0.154 mmol). After 5 minutes at room temperature, tert-butylisocyanate (0.01 mL, 0.077 mmol) was added and the reaction mixture was stirred at room temperature. After 16 hours, the reaction mixture was diluted with dichloromethane and washed with 1N HCl, saturated sodium bicarbonate, and brine. The dichloromethane layer was then evaporated to dryness under reduced pressure to give (2S,4R)-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-4-(5-chloropyridin-2-yloxy)-N-((2S)-1-cyclobutyl-4-(cyclopropylamino)-3-hydroxy-4-oxobutan-2-yl)pyrrolidine-2-carboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH:5]([NH2:8])[C:6]#[N:7])[CH3:2].N1C=CC=CC=1.[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:1]([O:3][C:4](=[O:9])[CH:5]([NH:8][C:24]([O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:25])[C:6]#[N:7])[CH3:2]
Reactant: CCOC(=O)C(N)C#N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C(C#N)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 60 %

Procedure:
To a stirred mixture of 2-amino-2-cyanoacetic acid ethyl ester (19.7 g) and pyridine (12.2 g) in water (123 ml) was added portionwise benzyloxycarbonyl chloride (27.9 g) under ice cooling. The resulting mixture was stirred under ice cooling for 1 hour. Precipitated crystals were collected, washed thoroughly with water, and recrystallized from ethanol to give the title compound (24.2 g, 60.2%) as colorless crystals, mp 111°-112° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CN(C=O)C.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[C:22]#[N:23])[NH:18][CH:17]=C2.[OH-].[Na+]>C(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[C:22]#[N:23])[NH:18][CH:17]=[C:2]2[CH:1]=[O:5]
Reactant: N#Cc1cc2[nH]ccc2cc1F
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc2[nH]cc(C=O)c2cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (0.68 mL) in DCM (10 mL) at 0° C. was dropwise added a solution of DMF (0.60 mL) in DCM (2 mL). The mixture was stirred for 0.5 h at 0° C. and then 5-fluoro-1H-indole-6-carbonitrile (D151) (250 mg) in DCM (3 mL) was added in one portion. The reaction mixture was allowed to warm to rt and stirred overnight. Afterwards, the reaction mixture was added with 2 M aqueous NaOH (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and then concentrated under vacuo to give the designed product 5-fluoro-3-formyl-1H-indole-6-carbonitrile (D152) (280 mg), which was used without purification. MS (ES): C10H5FN2O requires 188.0; found 189.1 (M+H+).
Reaction SMILES: [K].[S:2]([NH2:6])([NH2:5])(=[O:4])=[O:3].[C:7](OCC)(=[O:13])[C:8](OCC)=[O:9]>C(O)(C)C.CO>[OH:9][C:8]1[C:7]([OH:13])=[N:6][S:2](=[O:4])(=[O:3])[N:5]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: NS(N)(=O)=O
Agent: [K]
Solvent: CO
Solvent: CC(C)O
Product: O=S1(=O)N=C(O)C(O)=N1
Yield: 145 %

Procedure:
The compound was prepared according to Carmack et al. (J. Org. Chem. 1975, 40, 2743) as follows. Potassium metal (10.0 g, 0.26 mol) was dissolved in cool isopropanol (50 mL) which was then diluted with methanol (50 mL). A methanolic solution (100 mL) of sulfamide (12.32 g, 0.13 mol) was added dropwise with vigorous stirring, followed by dropwise diethyl oxalate (17.4 mL, 0.13 mol). The resulting mixture was heated at reflux for 18 hours. The mixture was cooled, filtered, and the solid was washed with methanol and dried to give 28.3 g of 3,4-dihydroxy-[1,2,5]thiadiazole-1,1-dioxide as the di-potassium salt. This was stirred with PCl5 (90.0 g, 0.43 mol) at 150° C. for 10 minutes. When enough POCl3 was generated to maintain stirring, the mixture was cooled to 60° C. and stirred for 18 hours. The reaction was cooled, diluted with diethyl ether, filtered, and washed with additional diethyl ether. The ether filtrate was added dropwise to ethanol (500 mL) at 0° C. The resulting solution was heated to reflux for 1.5 hours, cooled, and concentrated to 1/4 volume. The diethoxy derivative was collected as a white solid (4.80 g). The mother liquor afforded an additional 1.80 g. (Total yield: 26%): mp 171°-172° C. (Th. 178°-179° C.); 1H NMR (CDCl3): δ 4.59 (q, 4H), 1.50 (t, 6H).