Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.S(Cl)([Cl:16])=O>ClCCCl>[Cl:16][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1
Reactant: OCc1ccc(-n2cccn2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: ClCc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
To a solution of [4-(1H-pyrazol-1-yl)phenyl]methanol (24.0 g) in 1,2-dichloroethane (200 mL) was added dropwise thionyl chloride (26.3 g) under ice-cooling, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was washed with tert-butyl methyl ether to give the title compound (23.5 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[NH:6]2.CCN(P1(N(C)CCCN1C)=N[C:36]([CH3:39])([CH3:38])[CH3:37])CC.BrCC(C)=C>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[CH2:38][C:36]([CH3:39])=[CH2:37]
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)[nH]c12
Agent: C=C(C)CBr
Solvent: CN(C)C=O
Product: C=C(C)Cn1c(=O)[nH]c2c(N)nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
200 mg (0.531 mmol) of the compound from example 33 and 145 mg (0.531 mmol) of BEMP were initially charged in 10 ml of dimethylformamide, and a solution of 72 mg (0.531 mmol) of 3-bromo-2-methylprop-1-ene 2 ml of dimethylformamide was added dropwise at 0° C. within 10 min. The mixture was stirred at 0° C. for 1 h. Subsequently, the reaction solution was concentrated under reduced pressure and the residue was purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 10:90→90:10). 88 mg of the title compound were obtained (37% of theory).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]([C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:18])[C:16]#[N:17])=[CH:11][CH:10]=1)([CH2:7][CH3:8])[CH3:6].Cl.[CH:20]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)([CH2:22][CH3:23])[CH3:21]>ClC1C=CC=CC=1>[CH:5]([C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH3:18])[C:16]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([CH:20]([CH2:22][CH3:23])[CH3:21])=[CH:25][CH:26]=2)=[NH:17])=[CH:13][CH:14]=1)([CH2:7][CH3:8])[CH3:6]
Reactant: CCC(C)c1ccc(N)cc1
Reactant: CCC(C)c1ccc(N(C)C#N)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CCC(C)c1ccc(NC(=N)N(C)c2ccc(C(C)CC)cc2)cc1
Reaction time: 2 h
Yield: 52.1 %

Procedure:
Aluminum chloride (0.42 g, 3.1 mmol) was added to a stirred solution of N-4-sec-butylphenyl-N-methyl cyanamide (0.534 g, 2.84 mmol) in chlorobenzene (15 mL) at 145° C. After 10 minutes 4-sec-butylphenyl amine hydrochloride (0.474 g, 2.56 mmol, prepared from 4-sec-butyl aniline and 1.0 M HCl-ether) was added and continued reflux. After 2 hours, the reaction mixture was evaporated and the product was purified by flash chromatography to afford the title compound (0.45 g, 65%) as a syrup. TLC: Rf =0.22 (CH2Cl2 :CH3OH; 10:1); 1H NMR (CD3OD): δ 7.27 (d, 4H, J=8.18 Hz, ArH), 7.20 (d, 4H, J=8.36 Hz, ArH), 3.46 (s, 3H, --NCH3), 2.69-2.58 (m, 2H, 2× --CH), 1.68-1.57 (m, 4H, 2× --CH2), 1.25 (d, 6H, 2× --CH3), 0.85 (t, 6H, 2× --CH3); HRMS: 337.2484 (337.2528 Calcd. for C22H31N3); HPLC: (CH3CN:H2O; 50:50 with 0.1% TFA): 98% pure.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH:4]([CH:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH2:8][S:7]1)[CH3:5].S(Cl)(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][CH:2]([CH3:14])[CH2:3][CH:4]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH3:5]
Reactant: CC(C)CC(C)C1SCC=C1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(C)CC(C)c1sccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.1 %

Procedure:
After dissolving 2.8 g of 2-(4-methylpentan-2-yl)-3-nitro-2,5-dihydrothiophene in 40 ml of dichloromethane, a solution prepared by dissolving 2.6 g of sulfuryl chloride in 5 ml of dichloromethane was added thereto, and the solution was stirred at room temperature for 1.5 hours. After adding an aqueous solution of saturated sodium bicarbonate, the solution was extracted with dichloromethane. The organic layer was washed with saturated saline, dried with magnesium sulfate and concentrated, and then purified by NH-silica gel chromatography (hexane/ethyl acetate=10/1), thereby obtaining 2.0 g of 2-(4-methylpentan-2-yl)-3-nitrothiophene (yield: 70.1%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:51])[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[S:11]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]([S:39]([C:42]1[C:47]([CH3:48])=[CH:46][C:45]([CH3:49])=[CH:44][C:43]=1[CH3:50])(=[O:41])=[O:40])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([C:30]1[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=1[CH3:38])(=[O:29])=[O:28])(=[O:13])=[O:12].I[CH2:53][CH3:54].[CH3:55][CH2:56]CCCC.CCOC(C)=O>CN(C=O)C>[C:5]1([CH3:10])[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([CH3:51])[C:4]=1[S:11]([N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]([S:39]([C:42]1[C:43]([CH3:50])=[CH:44][C:45]([CH3:49])=[CH:46][C:47]=1[CH3:48])(=[O:40])=[O:41])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([S:27]([C:30]1[C:31]([CH3:38])=[CH:32][C:33]([CH3:37])=[CH:34][C:35]=1[CH3:36])(=[O:28])=[O:29])[CH2:53][CH3:54])[CH2:55][CH3:56])(=[O:13])=[O:12]
Reactant: CCI
Reactant: CCCCCC
Reactant: Cc1cc(C)c(S(=O)(=O)NCCCCCN(CCCCCNS(=O)(=O)c2c(C)cc(C)cc2C)S(=O)(=O)c2c(C)cc(C)cc2C)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CCCCCN(CCCCCN(CC)S(=O)(=O)c1c(C)cc(C)cc1C)S(=O)(=O)c1c(C)cc(C)cc1C)S(=O)(=O)c1c(C)cc(C)cc1C
Yield: 85 %

Procedure:
NaH (80%, 0.52 g, 17 mmol), 34 (3.2 g, 4.36 mmol), and iodoethane (1.5 g, 9.6 mmol) in DMF (20 mL) were reacted and worked up by the method of 43. Column chromatography (4:1 hexane/EtOAc) gave 2.91 g (85%) of 56 as a white solid: mp 60-62° C.; NMR δ 1.01 (t, 6 H, J=7), 1.08 (m, 4 H), 1.42 (m, 8 H), 2.29 (s, 9 H), 2.57 (s, 6 H), 2.58 (s, 12 H), 3.07 (t, 4 H, J=7), 3.11 (t, 4 H, J=7), 3.17 (q, 4 H), 6.92 (s, 6 H). Anal. (C41H63N3O6S3) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[Cl:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:28]=1[C:22]1([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:21][CH:20]2[CH2:29][C:30]([O:32]CC)=[O:31]>>[Cl:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:28]=1[C:22]1([CH2:23][CH2:24][N:25]([C:11](=[O:13])[CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH2:26][CH2:27]1)[CH2:21][CH:20]2[CH2:29][C:30]([OH:32])=[O:31]
Reactant: O=C(O)CCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Cl)cccc21
Product: O=C(O)CC1CC2(CCN(C(=O)CCc3ccc(Cl)cc3Cl)CC2)c2c(Cl)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 3-(2,4-dichlorophenyl)propanoic acid and ethyl 2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate followed by a procedure analogous to that in Example 2. LC-MS Method 1 tR=2.03, min, m/z=484, 482, 480
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][NH2:11].[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13]([CH3:15])=O>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10]/[N:11]=[C:13](/[CH3:15])\[C:12]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(C)=O
Reactant: NNc1cc(F)c(F)cc1Br
Solvent: CCO
Product: CCOC(=O)/C(C)=N\Nc1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 22 h
Yield: 100.2 %

Procedure:
A stirred solution of (2-bromo-4,5-difluoro-phenyl)-hydrazine (step A) (4.29 g, 19.2 mmol) in ethanol (13.8 ml) was cooled to 0° C. and a solution of ethyl pyruvate (2.39 g, 2.3 ml, 20.0 mmol) in ethanol (4 ml) was added drop wise at 0° C. for 15 min. After the mixture was allowed to stir at room temperature for 22 h it was evaporated to give crude (Z)-ethyl 2-[2-(2-bromo-4,5-difluoro-phenyl)-hydrazono]-propanoate (6.18 g, 100%) as light brown solid, MS (ISP) m/z=323.0 [(M+H)+], mp 78° C., which was used without further purification.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[CH3:21][O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:12][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)CCCCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)CCCCCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Benzenesulfonyl chloride (92a) (0.88 g, 5.0 mmol) was added to the mixture of methyl 6-aminohexanoate hydrochloride (91) (1.82 g, 10 mmol) in acetonitrile (10 ml) and sodium carbonate (2.6 g, 24.6 mmol) in water (10 ml). The mixture was stirred for 6 hours at ambient temperature, and the product was extracted with ethyl acetate (30 ml). The extract was dried (Na2SO4) and solvents were removed under reduced pressure. The product was chromatographed on silica gel with ethyl acetate-hexane (1:2) as eluent. The title compound was obtained as oil (1.28 g, 90%). 1H NMR δH (90 MHz, DMSO-d6) δ: 0.90-1.63 (6H, m, CH2); 2.21 (2H, t, J=7.0 Hz, CH2); 2.71 (2H, q, J=6.0 Hz, CH2N); 3.58 (3H, s, CH3); 7.40-7.72 (3H, m, C6H3); 7.72-7.89 (2H, m, C6H2).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[O-:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Na+]>CN1C(=O)CCC1.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:19][CH:18]=1)([CH3:21])[CH3:22]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Solvent: CN1CCCC1=O
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(Oc3ccccc3)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 37.5 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 100 mg, 0.302 mmol) and sodium phenoxide (70 mg, 605 mmol) in NMP (3 mL) was stirred at room temperature overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 40-50% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (44 mg, 37%). 1H NMR (DMSO-d6) δ: 11.11 (s, 1H), 8.21 (d, J=2.3 Hz, 1H), 7.91 (d, J=8.6 Hz, 2H), 7.41-7.68 (m, 7H), 7.17 (s, 1H), 6.51 (d, J=2.3 Hz, 1H), 3.94 (br. s., 1H), 1.43 (s, 6H). ESI-MS: m/z 389.0 (M+H)+.
Reaction SMILES: CO.S(=O)(=O)(O)O.[CH:8]([O:13][CH3:14])([O:11]C)OC.[C:15]([C:23]1C(=O)[O:25][C:26]([CH3:30])=[CH:27][C:28]=1[OH:29])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH3:14][O:13][C:8]([C:23]1[C:28](=[O:29])[CH:27]=[C:26]([CH3:30])[O:25][C:15]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:11]
Reactant: COC(OC)OC
Reactant: Cc1cc(O)c(C(=O)c2ccccc2)c(=O)o1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)oc(C)cc1=O
Yield: 75.8 %

Procedure:
A flask fitted with a reflux condenser and calcium chloride drying tube is charged with 70 ml dry methanol, 7.3 g of 96% sulfuric acid and 10.15 g of trimethyl orthoformate. 3-Benzoyl-4-hydroxy-6-methyl-2-pyrone (22 g) is then added in small portions and the resulting reaction mixture is refluxed for 24 hours. The mixture is cooled and poured into water. Extraction with methylene chloride yields 17.7 g of crude 3-methoxycarbonyl-6-methyl-2-phenyl-4-pyrone. mp (from methylene chloride/ether)=101°-102.5° C.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[C:15]#[C:16][Si](C)(C)C)([CH3:4])([CH3:3])[CH3:2].CCOC(C)=O>CN(C=O)C.[Cu]I>[C:1]([N:5]1[C:6]2[C:7](=[CH:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=2)[CH:15]=[CH:16]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Nc1ccc([N+](=O)[O-])cc1C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)n1ccc2cc([N+](=O)[O-])ccc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution of tert-butyl-(4-nitro-2-trimethylsilanylethynyl-phenyl)-amine (10 mg, 0.035 mmol) in DMF (2 mL), was added CuI (13 mg, 0.07 mmol) under N2 protection. The reaction mixture was stirred at 100° C. overnight. At this time, EtOAc (4 mL) was added to the mixture. The mixture was filtered and the filtrate was washed with water, brine, dried over Na2SO4 and concentrated under vacuum to obtain 1-tert-butyl-5-nitro-1H-indole (7 mg, 93%). 1H-NMR (CDCl3, 300 MHz) δ 8.57 (d, J=2.1 Hz, 1H), 8.06 (dd, J=2.4, 9.3 Hz, 1H), 7.65 (d, J=9.3 Hz, 1H), 7.43 (d, J=3.3 Hz, 1H), 6.63 (d, J=3.3 Hz, 1H), 1.76 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:24])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:23])=[CH:17]/[CH2:18][O:19]C(C)=O.CCOC1C=C2C(C)=CC(C)(C)NC2=CC=1>>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:24])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:23])=[CH:17]/[CH2:18][OH:19]
Reactant: CC(=O)OC/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C
Agent: CCOc1ccc2c(c1)C(C)=CC(C)(C)N2
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1

Procedure:
mixture of vitamin A acetate, 2.8 million IU/G unstab. (80% by weight) (BASF AG) and ethoxyquin (20% by weight) (Raluquin®, Raschig AG) was fed at 60° C. via a heated pump unit.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl>[CH:13](=[N:5][CH2:4][CH2:3][CH2:2][Br:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCCBr
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: BrCCCN=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
The hydrobromide salt of 3-bromopropylamine (5.364 g, 24.50 mmol) was treated with triethylamine (4 mL) in CHCl3 (100 mL) and allowed to stir at room temperature for 5 min. Benzaldehyde (2.000 g, 18.85 mmol) and magnesium sulfate (6.000 g) were added and the reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was filtered and the filter pad was washed with CHCl3 (50 mL). The filtrate was washed with water (3×50 mL), sat NaCl (50 mL), dried over sodium sulfate, and concentrated to provide a yellow oil (4.262 g, 100%). IR (film) 1645, 754, and 693 cm−1; 1H NMR (CDCl3) δ 8.34 (s, 1 H), 7.76 (m, 2 H), 7.44 (m, 3 H), 3.78 (dt, J=6.3 Hz and 1.3 Hz, 2 H), 3.52 (t, J=6.5 Hz, 2 H), 2.31 (pent, J=6.4 Hz, 2 H); ESIMS m/z (rel intensity) 226/228 (MH+, 100/91). Anal. (C10H12BrN) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:41][C@:42]1([C:47]([NH:49][S:50]([CH:53]2[CH2:55][CH2:54]2)(=[O:52])=[O:51])=[O:48])[CH2:44][C@H:43]1[CH:45]=[CH2:46].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO.CN(C=O)C>[CH:53]1([S:50]([NH:49][C:47]([C@@:42]2([NH:41][C:24]([C:23]3[CH:22]=[C:21]([C:18]4[CH:19]=[CH:20][C:10]5[O:9][C:8]([C:5]6[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=6)=[C:12]([C:13]([NH:14][CH3:15])=[O:16])[C:11]=5[CH:17]=4)[CH:29]=[CH:28][CH:27]=3)=[O:25])[CH2:44][C@H:43]2[CH:45]=[CH2:46])=[O:48])(=[O:52])=[O:51])[CH2:55][CH2:54]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C=C[C@@H]1C[C@]1(NC(=O)c1cccc(-c2ccc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3c2)c1)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 55.4 %

Procedure:
In a 7 mL scintillation vial were combined 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (30 mg, 0.077 mmol), (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide 4-methylbenzenesulfonate (30 mg, 0.075 mmol), and HATU (40 mg, 0.10 mmol). DMF (0.4 mL) and DIPEA (0.1 mL, 0.57 mmol) were added, the vial was capped, and the solution was stirred at r.t. for 45 min. The reaction was diluted with MeOH, filtered, purified by prep HPLC, and the collected fractions were concentrated on a speedvac to afford the title compound (25 mg, 54% yield) as a white powder. 1H NMR (500 MHz, CDCl3) δ ppm 8.01 (s, 1H) 7.97 (s, 1H) 7.88 (dd, J=8.85, 5.19 Hz, 2H) 7.80 (d, J=7.63 Hz, 1H) 7.74 (d, J=7.63 Hz, 1H) 7.59 (br. s., 1H) 7.52 (s, 2H) 7.48 (t, J=7.63 Hz, 1H) 7.18 (t, J=8.55 Hz, 2H) 6.00 (d, J=3.97 Hz, 1H) 5.61-5.73 (m, 1H) 5.39 (d, J=17.09 Hz, 1H) 5.20 (d, J=10.99 Hz, 1H) 3.02 (d, J=4.88 Hz, 3H) 2.91-2.99 (m, 1H) 2.34 (q, J=8.44 Hz, 1H) 2.05-2.09 (m, 1H) 1.49 (dd, J=9.31, 5.95 Hz, 1H) 1.41 (dd, J=5.80, 4.58 Hz, 1H) 1.30-1.35 (m, 1H) 1.22-1.30 (m, 1H) 1.04-1.12 (m, 1H) 0.96-1.04 (m, 1H). LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.73 min, (ES+) m/z (MH+)=602. Analytical HPLC were performed using a Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: solvent A=5% CH3OH/95% H2O/10 mM NH4HCO3, solvent B=95% CH3OH/5% H2O/10 mM NH4HCO3, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Phenomenex Gemini C18, 4.6 mm, 3 μm, Rt=16.26 min, purity=100%; column: Waters Xbridge Phenyl 4.6×150 mm, 3.5 μm, Rt=15.28 min, purity=100%.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[CH:18]/[CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([O:3]C)=[O:2].CO.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[CH:18]/[CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([OH:3])=[O:2]
Reactant: CCCCCC(O)/C=C/c1ccccc1CCCCCCC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCCCC(O)/C=C/c1ccccc1CCCCCCC(=O)O

Procedure:
A solution of 1.28 g. of 1-(6-carbomethoxyhexyl)- 2-(3-hydroxy-trans-1-octenyl)benzene in 150 ml. of methanol is cooled to 0° C. and a solution of 3.0 g. of potassium carbonate in 100 ml. of water is added. The ice bath is removed and the mixture is stirred for twenty-four hours. The methanol is removed in vacuo and the basic aqueous solution is washed with ether, cooled in ice and acidified to pH2 with dilute hydrochloric acid. The solution is then extracted with ether and the extract is washed with water and dried. The solvent is removed to yield 1-(6-carboxyhexyl)-2-(3-hydroxy-trans-1-octenyl)benzene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([C@@H:8]2[O:16][C@H:15]3[C@@H:10]([O:11][P:12]([NH:18][C@@H:19]([CH2:25][CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:17])[O:13][CH2:14]3)[C@:9]2([OH:28])[CH3:27])[C:4](=[O:29])[N:3]=1.CCN(CC)CC.[CH2:37]([CH:40]([CH2:44][CH2:45][CH3:46])[C:41](Cl)=[O:42])[CH2:38][CH3:39]>C1COCC1.CN(C=O)C.CN(C1C=CN=CC=1)C>[OH:28][C@:9]1([CH3:27])[C@@H:10]2[O:11][P:12]([NH:18][C@@H:19]([CH2:25][CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:17])[O:13][CH2:14][C@H:15]2[O:16][C@H:8]1[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:41](=[O:42])[CH:40]([CH2:44][CH2:45][CH3:46])[CH2:37][CH2:38][CH3:39])=[N:3][C:4]1=[O:29]
Reactant: CCCC(CCC)C(=O)Cl
Reactant: CCOC(=O)[C@H](CC)NP1(=O)OC[C@H]2O[C@@H](n3ccc(N)nc3=O)[C@](C)(O)[C@@H]2O1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(CCC)C(=O)Nc1ccn([C@@H]2O[C@@H]3COP(=O)(N[C@@H](CC)C(=O)OCC)O[C@H]3[C@@]2(C)O)c(=O)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
Ethyl (2S)-2-{[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl]amino}butanoate, prepared according the procedure described for Example 6, was diluted with a solution THF:DMF (5:2, 0.03 M). Et3N (4.0 eq.) and DMAP (0.2 eq.) were added then the mixture was cooled to 0° C. and 2-propylpentanoyl chloride (2.5 eq.) was added drop-wise. The mixture was immediately warmed to room temperature and stirred for 2 hours. The reaction was quenched by the addition of 1N HCl (aq) to bring the pH to 6, and then the solvent was removed in vacuum. The crude was purified by RP-HPLC (stationary phase: column Symmetry C18, 7 μm, 19×300 mm. Mobile phase: acetonitrile/H2O buffered with 0.1% TFA) to afford the title compound as white powder (36%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=1)[CH3:2].CC1C=CC(S(O[CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:10]([C:5]1[CH:6]=[C:7]([O:9][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=1)[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Reactant: CCc1cc(O)cc(CC)c1-c1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(OCCCS(C)(=O)=O)cc(CC)c1-c1cccc(C=O)c1
Temperature: 90 °C
Reaction time: 70 h
Yield: 79.6 %

Procedure:
To a solution of 2′,6′-diethyl-4′-hydroxybiphenyl-3-carbaldehyde (2.44 g, 9.59 mmol) and 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (3.36 g, 11.5 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.73 g, 12.5 mmol), and the mixture was stirred at 90° C. for 70 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30) to give the title compound (2.86 g, yield 80%) as a pale-yellow oil.
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:20]Br)=[CH:14][C:15]=2[N+:17]([O-:19])=[O:18])[C:10]([Br:22])=[C:9]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(OC(C)(C)C)=O.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Br:22][C:10]1[C:11]2[C:16](=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[C:13]([CH2:20][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:12]=2)[NH:8][C:9]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccccc2)c(Br)c2cc(CBr)cc([N+](=O)[O-])c21
Reactant: C1COCCN1
Product: O=[N+]([O-])c1cc(CN2CCOCC2)cc2c(Br)c(-c3ccccc3)[nH]c12

Procedure:
1-BOC-3-bromo-5-bromomethyl-7-nitro-2-phenyl-indole obtained in Step 2 of Preparation 63 and morpholine were reacted to give the title compound, according to the same procedures as Step 3 and 4 of Preparation 63.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[H][H]>N.[Ni]>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH2:11]
Reactant: [H][H]
Reactant: Cc1cccc(CC#N)c1C
Agent: [Ni]
Agent: N
Product: Cc1cccc(CCN)c1C
Yield: 66 %

Procedure:
A mixture of 2,3-dimethylphenylacetonitrile (J. Org Chem, 51(26), 5157-60; 1986), (190 mg, 1.31 mmol) and Raney® nickel (100 mg) in 2M methanolic ammonia (5 mL) was stirred under 50 psi of hydrogen gas for 4 days. The mixture was then filtered through Arbocel® and concentrated in vacuo to afford the title compound as a solid in 66% yield, 130 mg. 1H NMR (400 MHz, CDCl3) δ: 7.02-6.94 (3H, m), 2.26-2.13 (10H, m) ppm; LRMS ESI m/z 150 [M+H]+