Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[CH:15]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:14]([CH3:23])[C:13]2=[CH:24][CH:25]=1.O>C(O)C.O>[N:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[CH:15]([CH2:16][N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[CH:14]([CH3:23])[C:13]2=[CH:24][CH:25]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1c2ccc(OCCCBr)cc2C1CN1CCCCC1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1c2ccc(OCCCN=[N+]=[N-])cc2C1CN1CCCCC1

Procedure:
Sodium azide (1.49 g) is added to a stirred solution of 5-(3-bromopropoxy)-2-methyl-1-(1-piperidinylmethyl)benzocyclobutene (7.3 g) dissolved in a mixture of ethanol/water (7.3 ml/73 ml). The reaction mixture is refluxed overnight, poured into water and extracted with ether. The organic extract is washed with sat'd aqueous NaCl, dried, filtered and evaporated in vacuo affording the desired product as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:18])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[Li]C(C)(C)C.[CH3:24][O:25][CH2:26][CH2:27][N:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH:33]=[O:34]>C1COCC1.CCCCC>[OH:34][CH:33]([C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:18])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1)[C:29]1[N:28]([CH2:27][CH2:26][O:25][CH3:24])[CH:32]=[CH:31][CH:30]=1
Reactant: COCCn1cccc1C=O
Reactant: CN(c1ccc(Br)cc1)S(=O)(=O)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COCCn1cccc1C(O)c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1
Temperature: -30 °C

Procedure:
To a solution of 1.49 g (4.59 mmol) of N-(4-bromophenyl)-N-methyl benzenesulfonamide (see Preparative Example A, Step C) in 37.5 mL THF at −78° C. was added dropwise 5.94 mL (10.10 mmol) of a 1.7 M solution of tert-BuLi in pentane and the resultant mixture was stirred at −78° C. for 15 min. To this mixture was then added a solution of 1.01 g (6.59 mmol) of N-methoxyethylpyrrole-2-carboxaldehyde in 6 mL THF and the mixture was allowed to gradually warm to −30° C. over a 4 h period. After this time, the reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 13:7) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:16])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][N:29]([C:32](Cl)=[O:33])[C:28]1=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:32]([N:29]3[CH2:30][CH2:31][N:27]([CH2:26][CH2:25][O:24][CH3:23])[C:28]3=[O:35])=[O:33])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(N)ccc1Oc1ccnc(Cl)c1
Reactant: COCCN1CCN(C(=O)Cl)C1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCN1CCN(C(=O)Nc2ccc(Oc3ccnc(Cl)c3)c(C)n2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
A 0° C. mixture of Example A7 (0.350 g, 1.485 mmol) and pyridine (0.251 mL, 3.12 mmol) in DCM (10 mL) was treated with a solution of Example B4 (0.368 g, 1.782 mmol) in DCM (5 mL) and stirred at RT overnight. The mixture was treated with satd. NaHCO3, extracted with DCM (2×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified twice via silica gel chromatography (MeOH/DCM) to afford N-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(2-methoxyethyl)-2-oxoimidazolidine-1-carboxamide (487 mg, 81%) as a yellow oil. MS (ESI) m/z: 406.1 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:60]=[CH:61][CH:62]=1)[CH2:45][N:46]1[CH2:50][CH2:49][N:48]([C@@H:51]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:52](O)=[O:53])[C:47]1=[O:59].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:52](=[O:53])[C@@H:51]([N:48]1[CH2:49][CH2:50][N:46]([CH2:45][C:44]2[CH:60]=[CH:61][CH:62]=[C:42]([O:41][CH3:40])[CH:43]=2)[C:47]1=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: COc1cccc(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)c1
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(OC)c2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
A solution containing the product from Example 1H (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 71A (0.018 g, 0.056 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.033 mL, 0.189 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed brine, dried over MgSO4, filtered and concentrated to give the title compound (0.018 g, 54% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (s, 9 H), 0.87 (s, 9 H), 1.25 (m, 1 H), 1.39 (m, 1 H), 1.54 (m, 1 H), 2.42 (m, 1 H), 2.64 (m, 3 H), 2.89 (m, 2 H), 3.21 (m, 1 H), 3.54 (m, 4 H), 3.72 (s, 3 H), 3.84 (d, J=9.56 Hz, 1 H), 3.96 (m, 1 H), 4.04 (s, 1 H), 4.18 (m, 1 H), 4.27 (s, 2 H), 4.44 (d, J=6.99 Hz, 1 H), 6.85 (m, 4 H), 7.06 (m, 5 H), 7.29 (m, 4 H), 7.54 (d, J=9.56 Hz, 1 H), 7.89 (m, 5 H), 8.65 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[CH:25]=3)[CH2:20][CH2:19]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(C)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 8 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.32–7.24 (m, 7H), 6.91 (d, 1H, J=7.2 Hz), 6.67 (m, 1H), 3.31 (q, 2H, J=5.5 Hz), 2.92–2.85 (m, 2H), 2.53 (septet, 1H, J=6.7 Hz), 2.43 (tt, 1H, J=11.6, 3.0 Hz), 2.33 (t, 2H, J=6.7 Hz), 1.91 (dt, 2H, J=11.7, 1.8 Hz), 1.78–1.72 (m, 2H), 1.65–1.59 (m, 2H), 1.56 (s, 6H), 1.52–1.45 (m, 2H), 1.25 (d, 6H, J=6.7 Hz); ESMS m/e: 484.3 (M+H)+; Anal. Calc. for (HCl salt) C28H38ClN3O2.HCl.0.30 CHCl3: C, 61.10; H, 7.12; N, 7.55. Found: C, 60.90; H, 7.20; N, 7.64.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([O-:4])=O.[CH3:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14].[O-]CC.[Na+].OS(O)(=O)=O>C(O)C.O>[O:4]=[C:2]([CH2:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCCCC(C)=O
Reactant: CCOC(=O)C(=O)[O-]
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCC(=O)CC(=O)C(=O)OCC
Temperature: 0 °C
Yield: 80.4 %

Procedure:
A mixture of ethyl oxalate (97.21 g) and hexan-2-one (66.58 g) was added dropwise to a solution of sodium ethoxide (50.1 g) in ethanol (160 ml) at reflux. The resultant mixture was heated at reflux for 2 h. The cooled reaction mixture was poured into a stirring mixture of ice (500 g) and water (100 ml) and the resultant slurry adjusted to pH 1.5(conc.H2SO4). The two layers were separated and the bottom layer extracted with toluene (2×200 ml). The combined organics were washed with brine (200 ml), dried and concentrated in vacuo to give a residue (107 g) which was purified by distillation to afford the title compound as a colourless liquid (67.2 g).
Reaction SMILES: C(OCC(COC(=O)C)CCN1C=NC2C1=NC(N)=NC=2)(=O)C.OCC(CO)CCN1C=NC2C(=O)NC(N)=NC1=2.[NH2:42][C:43]1[N:51]=[C:50]2[C:46]([NH:47][CH:48]=[N:49]2)=[C:45]([Cl:52])[N:44]=1.Br[CH2:54][CH2:55][C:56]([C:67]([O:69]CC)=[O:68])([C:62]([O:64][CH2:65][CH3:66])=[O:63])[C:57]([O:59][CH2:60][CH3:61])=[O:58]>>[NH2:42][C:43]1[N:51]=[C:50]2[C:46]([N:47]=[CH:48][N:49]2[CH2:54][CH2:55][C:56]([C:67]([OH:69])=[O:68])([C:57]([O:59][CH2:60][CH3:61])=[O:58])[C:62]([O:64][CH2:65][CH3:66])=[O:63])=[C:45]([Cl:52])[N:44]=1
Reactant: CCOC(=O)C(CCBr)(C(=O)OCC)C(=O)OCC
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: CC(=O)OCC(CCn1cnc2cnc(N)nc21)COC(C)=O
Agent: Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Product: CCOC(=O)C(CCn1cnc2c(Cl)nc(N)nc21)(C(=O)O)C(=O)OCC

Procedure:
Nucleosides and Nucleotides, 15(5), 981-994 (1996) and WO 95/28402 disclose a process for the manufacture of the anti-viral agents 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-aminopurine (famciclovir) and 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (penciclovir). According to this process, the ‘bromoester’ route, 2-amino-6-chloropurine is reacted with triethyl 3-bromopropane-1,1,1-tricarboxylate in the presence of base to form diethyl 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]-2-carboxymalonate. The crude isolate from this alkylation reaction is then treated with sodium methoxide in methanol to form dimethyl 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]malonate. This product is purified by crystallisation and then successively reduced using sodium borohydride and O-acetylated to give 9-(4-acetoxy-3-acetoxymethylbutyl)-2-amino-6-chloropurine. Famciclovir is produced directly from the latter compound by hydrogenation over a supported palladium catalyst; and penciclovir is produced from this compound by acid hydrolysis of the acetoxy groups.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:10]([C:11]([O:13]C)=[O:12])[S:9][CH2:8][C:7](=[O:15])[C:6]=2[CH:16]=1.[OH-].[K+].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:10]([C:11]([OH:13])=[O:12])[S:9][CH2:8][C:7](=[O:15])[C:6]=2[CH:16]=1
Reactant: COC(=O)C1SCC(=O)c2cc(Cl)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1CSC(C(=O)O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
In methanol (100 ml) was suspended methyl 6-chloro-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate (21.5 g) followed by addition of 2N-KOH (70 ml). The mixture was stirred at room temperature for one hour. The resulting reaction mixture was poured into water, acidified and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and the solvent was distilled off to give 6-chloro-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (18.8 g, yield 93%). Recrystallization from ethyl acetate gave colorless prisms.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C@@H:13]([CH3:14])[C@H:12]([OH:15])[C:11]([F:17])([F:16])[C:10]2=[O:18])[CH:5]=[CH:6][C:7]=1I.O.[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C@@H:13]([CH3:14])[C@H:12]([OH:15])[C:11]([F:17])([F:16])[C:10]2=[O:18])[CH:5]=[CH:6][C:7]=1[C:20]#[N:21]
Reactant: C[C@H]1[C@H](O)C(F)(F)C(=O)N1c1ccc(I)c(Cl)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: C[C@H]1[C@H](O)C(F)(F)C(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a solution of (4S,5S)-1-(3-chloro-4-iodophenyl)-3,3-difluoro-4-hydroxy-5-methylpyrrolidin-2-one (113 mg) in DMF (3.5 mL) were added zinc cyanide (12 mg) and tetrakis(triphenylphosphine)palladium(0) (34 mg), and the mixture was stirred at 100° C. for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/2) to give the title compound as a colorless solid (yield: 75 mg, 90%).
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[OH-].[K+].[N:12](OCCC(C)C)=[O:13]>C(O)C>[CH3:1][C:2]1[C:8]([OH:9])=[C:7]([N:12]=[O:13])[CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: Cc1c(O)cccc1O
Reactant: CC(C)CCON=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(O)ccc(N=O)c1O
Reaction time: 3 h

Procedure:
19.8 g. 2-Methylresorcinol and 13.4 g. potassium hydroxide are dissolved in 120 ml. ethanol and cooled to 5° C. 24 ml. Isopentyl nitrite are added dropwise thereto, the reaction mixture is stirred for 3 hours and the precipitate is filtered off with suction. The yellow solid material is stirred into 200 ml. 5N sulphuric acid, the bright yellow product thereby precipitating out. Yield 22 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[NH:17][CH2:16][CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)=[CH:3][CH:2]=1.[H-].[Na+].[C:20]1([CH2:26][CH2:27][C:28](Cl)=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[C:20]1([CH2:26][CH2:27][C:28]([N:17]2[C:9]3=[N:8][C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[CH:12][C:11](=[O:13])[N:10]3[CH2:14][CH2:15][CH2:16]2)=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1cc(-c2ccncc2)nc2n1CCCN2
Reactant: O=C(Cl)CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(CCc1ccccc1)N1CCCn2c1nc(-c1ccncc1)cc2=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 0.2 g (0.87 mmol) of 2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 5 ml of chloroform was treated with 26 mg (1.14 mmol) of sodium hydride (60% suspension in mineral oil) and the resulting mixture was stirred at room temperature for 15 min and then cooled to 0° C. 0.148 g (0.964 mmol) of 3-phenylpropionyl chloride was added and the reaction mixture was stirred at room temperature during 18 h.
Reaction SMILES: [CH2:1]([C:4]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])=[CH:7][NH:8]2)[CH:2]=[CH2:3].C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH2:1]([C:4]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]([CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH2:7][NH:8]2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)ccc2[nH]cc(CCNC(=O)CC)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=CCc1c(O)ccc2c1C(CCNC(=O)CC)CN2
Temperature: 15 °C
Reaction time: 1 h

Procedure:
To a solution of N-[2-(4-allyl-5-hydroxyindol-3-yl)ethyl]propionamide (3.73 g, 14.3 mmol) in acetic acid (20 mL) was added sodium cyanoborohydride (2.7 g, 43.0 mmol) portionwise maintaining the reaction temperature around 15° C. The mixture was stirred for 1 hour maintaining the temperature 15 to 20° C. and then poured into water. The product was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, brine and water, dried over anhydrous magnesium sulfate and evaporated to afford the title compound. This compound was used for the subsequent reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[Li]C(CC)C.C1CCCCC1.CN(C)[CH:38]=[O:39].[NH4+].[Cl-]>O1CCCC1>[C:1]([O:5][C:6](=[O:24])[N:7]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:38]=[O:39])=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCCCCCCN(CCc1ccc(Br)cc1)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCCCCCCN(CCc1ccc(C=O)cc1)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of [2-(4-bromo-phenyl)-ethyl]-heptyl-carbamic acid tert-butyl ester (20 g, 50.2 mmol) dissolved in tetrahydrofuran (200 mL) under a nitrogen atmosphere at −78° C. was added 1.3 M sec-BuLi in cyclohexane (100.5 mmol, 77.3 mL) dropwise. The solution was allowed to stir at −78° C. for 30 minutes. Anhydrous N,N-dimethylformamide (150.6 mmol, 11.6 mL) was added in one portion and the solution was allowed to warm to room temperature. After stirring for 30 minutes the mixture was poured over saturated NH4Cl solution and extracted with diethyl ether (3×). The organic layers were combined, washed with water (1×), saturated brine (2×), dried over Na2SO4 and concentrated to a crude yellow oil. The oil was purified by chromatography on silica gel (Merck silica gel 60, art#9385-3) eluting with 20% ethyl acetate in hexanes to give impure [2-(4-formyl-phenyl)-ethyl]-heptyl-carbamic acid tert-butyl ester as a clear oil used directly in the following procedure. (11.62 g crude).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: BrCCCCC1CCCCO1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCCCC1CCCCO1

Procedure:
Prepared similarly to Intermediate 213 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(4-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][N:30]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:17][C:16]=2[C:31]#[N:32])=[CH:11][C:10]=1[C:33]#[N:34])C1C=CC=CC=1.B(O)(O)O.C(C1C=C(C2C=C(C=CN=2)C(OC)=O)C=CC=1OS(C(F)(F)F)(=O)=O)#N.[H][H]>C1COCC1.CO.[C].[Pd]>[C:31]([C:16]1[CH:17]=[C:18]([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][N:30]=2)[C:24]([O:26][CH3:27])=[O:25])[CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([C:33]#[N:34])[CH:11]=1)#[N:32]
Reactant: [H][H]
Reactant: COC(=O)c1ccnc(-c2ccc(-c3ccc(OCc4ccccc4)c(C#N)c3)c(C#N)c2)c1
Agent: [Pd]
Agent: COC(=O)c1ccnc(-c2ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c2)c1
Agent: OB(O)O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccnc(-c2ccc(-c3ccc(O)c(C#N)c3)c(C#N)c2)c1
Yield: 47.5 %

Procedure:
1.32 g of methyl 2-[4′-(benzyloxy)-2,3′-dicyanobiphenyl-4-yl]isonicotinate, which had been obtained in the same manner as in Example 1(1) using 4-(benzyloxy)-3-cyanophenyl]boric acid and methyl 2-(3-cyano-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)isonicotinate, was dissolved in a mixture of 50 ml of THF and 50 ml of methanol, and 0.5 g of palladium-carbon was added, followed by stirring in a hydrogen atmosphere at room temperature for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 0.5 g of methyl 2-(2,3′-dicyano-4′-hydroxybiphenyl-4-yl)isonicotinate.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][CH:11]=2)[N:4]=[CH:3]1.[Li]CCCC.[I:18]I.[NH4+].[Cl-]>C1COCC1>[I:18][C:3]1[N:2]([CH3:1])[CH:6]=[C:5]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][CH:11]=2)[N:4]=1
Reactant: Cc1ccc(-c2cn(C)cn2)s1
Reactant: II
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cn(C)c(I)n2)s1
Temperature: -40 °C
Reaction time: 8 h
Yield: 106.5 %

Procedure:
A mixture of 1-methyl-4-(5-methylthiophen-2-yl)-1H-imidazole 5 (2.36 g, 13.3 mmol) in THF (0.100 mL) was cooled −78° C. nBuLi (9.53 mL of a 1.6 M solution in hexanes, 15.2 mmol) was added dropwise (˜2 min) and the pale yellow solution was allowed to warm to −40° C. (over ˜1 h) and then re-cooled to −78° C. I2 (2.74 g, 10.4 mmol) was added and the mixture was allowed to warm to room temperature (over ˜2 h) and stirred overnight. Saturated aqueous NH4Cl (2 mL) was added and the mixture was concentrated to ˜10 mL. The mixture was diluted with CH2Cl2. H2O, saturated aqueous Na2S2O3 and the organic phase was separated. The aqueous phase was re-extracted (CH2Cl2) and the combined organics were washed (saturated aqueous NaCl), dried (MgSO4), filtered and concentrated to give a residue. The residue was purified by flash chromatography (EtOAc/hexanes 10:90 then 15:85 then 25:75) to give 2-iodo-1-methyl-4-(5-methylthiophen-2-yl)-1H-imidazole 6 (3.37 g, 84%) as a colourless solid. 1H NMR (CDCl3, 400 MHz) δ2.46 (d, J=0.8 Hz, 3H), 3.59 (s, 3H), 6.62-6.66 (m, 1H), 7.04 (d, J=3.5 Hz, 1H), 7.11 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ15.3, 36.8, 91.0, 118.7, 122.2, 125.5, 134.3, 138.1, 140.5; HRMS (EI) m/z 303.9533 C9H9N21S [M]+. requires 303.9526.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:15])[CH2:6][S:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:18]I>CN(C)C=O>[CH3:18][N:4]([C:1](=[O:3])[CH3:2])[C:5](=[O:15])[CH2:6][S:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)NC(=O)CSCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)C(=O)CSCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 11.15 g. (0.05 mole) of the product of Step A above in 75 ml. of dimethylformamide was cooled to -5° C. and there was then added 2.4 g. (0.05 mole) of 50% sodium hydride. The reaction mixture was aged for 30 minutes at -5° C., after which there was added 3.2 ml. (0.05 mole) of methyl iodide, and the reaction mixture was aged for 1 hour, 15 minutes at 0° C. and 45 minutes at room temperature. The reaction mixture was poured into ice water, seeded and placed in a refrigerator overnight. It was then filtered, washed with water and air dried. A yield of 9.0 g. of product was obtained.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.Br[C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:32](=[O:41])/[CH:33]=[CH:34]/[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:16][C:17]([N:19]2[CH2:23][CH2:22][C@H:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20]2)=[O:18])=[CH:11][CH:10]=1>ClCCl>[NH2:24][C@H:21]1[CH2:22][CH2:23][N:19]([C:17](=[O:18])[CH2:16][N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:5][C:3]3[CH:2]=[CH:11][CH:10]=[CH:9][CH:14]=3)=[CH:10][CH:11]=2)[C:32](=[O:41])/[CH:33]=[CH:34]/[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(Br)cc2)C1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(Oc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
Trifluoroacetic acid (30 mL) was added to a solution of [(S)-1-(2-{(4-bromophenyl)-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]carbamic acid, tert-butyl ester 3 (4.0 g, 7.57 mmol) in dichloromethane (90 mL). The reaction mixture was stirred at room temperature for 16 h, and then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1M NaOH (×2), brine, dried (Na2SO4) and evaporated to give the title compound as a foam (2.78 g, 86%). 1HNMR (300 MHz) (d6-DMSO) δ 1.5-2.1 (2H, 4×m), 3.08 (1H, m), 3.1-3.6 (4H, m), 4.47, 4.50 (2H, 2×br s), 6.43 (1H, br d), 7.3-7.5 (7H, m), 7.53 (1H, d, J=16 Hz) and 7.65 (2H, d).