Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[C:16]2[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)=[N:14][CH:13]=[N:12][C:11]=2[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:9]=1)=O)(=[O:3])[CH3:2].N1C=CN=C1.C(Br)(Br)(Br)Br.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>ClCCl>[CH3:2][C:1]1[O:3][C:6]([C:8]2[C:16]3[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=4)=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[CH:9]=2)=[N:5][N:4]=1
Reactant: CC(=O)NNC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc([N+](=O)[O-])c3)c12
Agent: BrC(Br)(Br)Br
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnc(-c2cn(COCC[Si](C)(C)C)c3ncnc(-c4cccc([N+](=O)[O-])c4)c23)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N′-acetyl-4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbohydrazide (470 mg, 1.00 mmol) in dichloromethane (10 mL) was added imidazole (0.15 g, 2.2 mmol), CBr4 (0.72 g, 2.2 mmol) and PPh3 (0.58 g, 2.2 mmol). The reaction was stirred for 1 hour at room temperature and then concentrated in vacuo. The reaction was purified by chromatography using silica gel, eluting with 1-20% ethyl acetate/petroleum ether. The product was collected and concentrated in vacuo to afford 2-methyl-5-(4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1,3,4-oxadiazole as a white solid. 1NMR (300 MHz, CD3OD) δ 9.08 (s, 1H), 8.45-8.34 (m, 3H), 8.01-7.98 (m, 1H), 7.74-7.53 (m, 1H), 5.87 (s, 2H), 3.74-3.69 (m, 2H), 2.29 (s, 3H), 0.98-0.93 (m, 2H), 0.02 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([C:18]([O:20]CC)=[O:19])=[C:16]([CH3:23])[CH:15]=[C:14]([CH3:24])[N:13]=1>Cl>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([C:18]([OH:20])=[O:19])=[C:16]([CH3:23])[CH:15]=[C:14]([CH3:24])[N:13]=1
Reactant: CCOC(=O)c1c(C)cc(C)nc1NCCSCc1nc[nH]c1C
Agent: Cl
Product: Cc1cc(C)c(C(=O)O)c(NCCSCc2nc[nH]c2C)n1
Yield: 8.9 %

Procedure:
Ethyl 2-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amino-4,6-dimethylpyridine-3-carboxylate (2.45 g, 0.0070 moles) was hydrolysed by refluxing with an excess of conc. hydrochloric acid (20 ml) for 20 hours. The reaction mixture was next evaporated to dryness, dissolved in a little water and basified to ph7.5 using 2N sodium hydroxide solution. After evaporating off water, the residue was dissolved in ethanol and adsorbed onto silica gel, followed by chromatography on silica gel using chloroform/methanol (10:1). The crude product was recrystallised from water to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amino-4,6-dimethyl pyridine-3-carboxylic acid (0.20 g) which sublimes with decomposition above 110°. NMR data:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[Cl:7][C:8]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=1[CH2:10]Br>>[Cl:7][C:8]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=1[CH2:10][N:4]1[CH:5]=[CH:6][C:2]([NH2:1])=[N:3]1
Reactant: Clc1ccc(CBr)c(Cl)c1
Reactant: Nc1cc[nH]n1
Product: Nc1ccn(Cc2ccc(Cl)cc2Cl)n1

Procedure:
Prepared in analogy to example 10a) starting with 3-amino-1H-pyrazole and 2,4-dichlorobenzyl bromide. The title compound was obtained as a light yellow solid (Yield=52%). MS ISP (m/e): 242.2 (100) [(M+H)+].
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][NH:24][CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)=[CH:9][C:6]=1[C:7]#[N:8])[CH3:3].C(N(CC)C(C)C)(C)C.Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>C(#N)C>[C:7]([C:6]1[CH:9]=[C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][N:24]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:11]=[CH:12][C:5]=1[O:4][CH:2]([CH3:1])[CH3:3])#[N:8]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCNC4)no2)cc1C#N
Reactant: CCOC(=O)CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1CCOc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)C1
Temperature: 80 °C
Yield: 96.5 %

Procedure:
To a solution of 2-[(1-methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)-1,2,4-oxadiazol-5-yl]benzonitrile (Example 32) (110 mg, 0.224 mmol) in acetonitrile (10 mL) was added N,N-diisopropylethylamine (0.08 mL, 0.449 mmol) and ethyl bromoacetate (0.05 mL, 0.449 mmol). The reaction mixture was heated to 80° C. for 2 hours. The mixture was allowed to cool to room temperature. The solvent was evaporated to give the title compound as a brown solid (100 mg).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([Cl:17])[CH:10]=[CH:11][CH:12]=3)[C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl.Cl.C(O)(=O)C>CCOCC>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([Cl:17])[CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C1c2cccc(Cl)c2Cc2cccc(Cl)c21

Procedure:
1,5-dichloroanthraquinone (1) was reduced with SnCl2 in boiling HCl and acetic acid with ether cleavage to give the corresponding 1,5 dichloro-9(10H)-anthracenone (II). To a solution of 1,5-dichloro-9(10H)anthracenone (1 mmol) and 0. 1 mL of pyridine in dry CH2Cl2 (20 mL) was added dropwise a solution of an appropriate acyl chloride (3 mmol) in dry CH2Cl2 (10 mL) under N2. The reaction mixture was stirred at room temperature or refluxed for several hours. The solvent was removed and the residue purified by recrystallization and chromatography. This procedure was used to synthesize each of the compounds in Table 1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH:10]1([C:13]2[NH:17][N:16]=[C:15]([NH2:18])[CH:14]=2)[CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C>C(O)CCC.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:18][C:15]2[CH:14]=[C:13]([CH:10]3[CH2:12][CH2:11]3)[NH:17][N:16]=2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2cc(C3CC3)[nH]n2)nc(Cl)n1
Temperature: 60 °C
Yield: 50.1 %

Procedure:
A mixture of 2,4-dichloro-6-methylpyrimidine (30.0 g, 184 mmol), 5-cyclopropyl-1H-pyrazol-3-ylamine (22.6 g, 184 mmol) and diisopropylethylamine (46 mL, 278 mmol) in 1-butanol (50 mL) was heated to 60° C. for 65 h. The reaction was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with 2 N sodium hydroxide, water and brine, then dried over sodium sulfate and concentrated on a rotary evaporator. The residue was treated with a small amount of acetonitrile, sonicated and then triturated with ether until a solid was formed. The solid was collected by filtration to give the desired product (23.0 g, 50%) as a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][CH:9]([CH:18]([OH:31])[CH2:19][O:20][C:21]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[C:23]([F:29])[C:22]=1[F:30])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]1[C:42](O)=[O:43].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]1[C:42]([NH:1][C@H:2]([C:6]([NH:8][CH:9]([CH:18]([OH:31])[CH2:19][O:20][C:21]1[C:22]([F:30])=[C:23]([F:29])[CH:24]=[C:25]([F:28])[C:26]=1[F:27])[CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:43]
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)COc1c(F)c(F)cc(F)c1F
Reactant: Cn1c(C(=O)O)cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)COc1c(F)c(F)cc(F)c1F
Yield: 58.2 %

Procedure:
The procedure of Example 77 was followed using the product of Example 106 (197.0 mg, 0.44 mmol), 1-methylindole-2-carboxylic acid (152 mg, 0.87 mmol), NMM (0.047 ml, 0.44 mmol), HOBt (144 mg, 0.96 mmol), and EDAC (183 mg, 0.96 mmol) in methylene chloride to prepare the titled product (156 mg, 58%).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].C(Cl)CCl.O[C@H:13]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:14][NH:15][C:16]([C@@H:18]([CH2:27][CH:28]=[CH2:29])[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17].CCN(C(C)C)C(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:1]([O:7][C@H:13]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:14][NH:15][C:16]([C@@H:18]([CH2:27][CH:28]=[CH2:29])[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CC[C@@H](CC(=O)OC(C)(C)C)C(=O)NC[C@H](O)c1ccccc1
Reactant: C=CCCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCC(=O)O[C@@H](CNC(=O)[C@@H](CC=C)CC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
To a solution of 4-pentenoic acid (0.335 mL, 3.28 mmol) in DMF (31.6 mL) cooled in an ice/water bath was added EDC (630 mg, 3.28 mmol) and the resulting solution was stirred 30 min. (S)-tert-butyl 3-((R)-2-hydroxy-2-phenylethylcarbamoyl)hex-5-enoate (730 mg, 2.19 mmol), iPr2NEt (1.14 mL, 6.57 mmol) and DMAP (26.7 mg, 0.219 mmol) were subsequently added and the reaction mixture was slowly warmed to rt and stirred for 16 h at which point LC-MS analysis indicated complete consumption of starting material. The reaction mixture was diluted with saturated NH4Cl and EtOAc and the layers separated. The aqueous was extracted 2× with EtOAc and the combined organic extracts were washed with 1N HCl and brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified using silica gel chromatography (MeOH/CH2Cl2 gradient) to yield 670 mg of desired product as a colorless oil in 74% yield. LRMS (M+Na)+: 430.0.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C@H:10]3[CH2:12][C:13](=[O:16])[CH2:14][CH2:15][C@H:9]3[C:8]([CH3:18])([CH3:17])[O:7][C:6]=2[CH:5]=[C:4]([C:19]([CH3:27])([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:3]=1>C(Cl)(Cl)Cl>[OH:1][C:2]1[C:11]2[C@@H:10]3[CH2:12][C:13](=[O:16])[CH2:14][CH2:15][C@H:9]3[C:8]([CH3:17])([CH3:18])[O:7][C:6]=2[CH:5]=[C:4]([C:19]([CH3:26])([CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:3]=1
Reactant: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(=O)C[C@H]21
Solvent: ClC(Cl)Cl
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(=O)C[C@@H]21

Procedure:
Evaporation of the solvent from eluates shown by thin layer chromatography to contain a different component afforded 55 mg. of (-)-cis-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo-[b,d]pyran-9-one. [α]20D - 50° (c = 1.0, CHCl3).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[S:11][C:10]=2[CH2:24][CH3:25])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:28])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:28][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[S:11][C:10]=1[CH2:24][CH3:25]
Reactant: CCc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Cl)C1CCCCC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of cyclohexyl{2-ethyl-5-[4-(trifluoromethyl)phenyl]thiophen-3-yl}methanol (2.29 g) synthesized in Example 69 (7) in toluene (25 mL) was added thionyl chloride (907 μL), and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was cooled to 0° C., saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title compound (2.08 g, 86%) as a pale-brown solid.
Reaction SMILES: S(O[C@H:12]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C)P(=O)(N(C)C)N(C)C>[N:39]([C@@H:12]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13]1)=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]43)C2)cc1
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](N=[N+]=[N-])CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C

Procedure:
4 g (7.37 mmol) 3β-tosyloxy-5α-cholestane and 0.99 g (15.23 mmol) NaN3 are heated under stirring in 25 ml hexamethylphosphoric acid triamide (HMPT) for 3 h to 90° C. The reaction mixture is cooled and given into 100 ml ice water, the precipitated raw product subsequently removed by filtration, washed with water and dissolved in 60 ml ether. The organic phase is washed twice with water, dried over Na2SO4 and concentrated. The resulting wax-like product is directly processed further:
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][N:8]([C@@H:14]3[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:20]([O:21][C:22](=[O:25])[CH2:23][CH3:24])[C@H:15]3[O:16][C:17](=[O:19])[CH3:18])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[CH3:34][O:35][C:36](=[O:39])[CH2:37][NH2:38].C[O-].[Na+]>CO>[CH3:34][O:35][C:36](=[O:39])[CH2:37][NH:38][C:2]1[C:3]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][N:8]([C@@H:14]3[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:20]([O:21][C:22](=[O:25])[CH2:23][CH3:24])[C@H:15]3[O:16][C:17](=[O:19])[CH3:18])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2cc([N+](=O)[O-])c3c(Cl)ncnc32)O[C@@H]1COC(C)=O
Reactant: COC(=O)CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2cc([N+](=O)[O-])c3c(NCC(=O)OC)ncnc32)O[C@@H]1COC(C)=O
Temperature: 75 °C

Procedure:
The compound from Step 3 (150 mg, 0.319 mmol) was dissolved in anhydrous MeOH (3 mL). Meanwhile glycine methylester mono hydrochloride (48 mg, 0.383 mmol) was neutralized with a 0.5M solution NaOMe (766 μl, 0.383 mmol) and this mixture was added to the methanolic solution containing nucleoside and the mixture was heated to 75° C. for 1.5 hours. Concentrated reaction in vacuo and purified on flash silica gel chromatography with a 0-5.0% MeOH gradient in DCM to afford 100 mg (60%).
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34][C:35]([C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)([F:39])[C:36]([OH:38])=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.Cl.[N:49]1([C:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[N:58]=[CH:57][N:56]=2)[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:25]([O:29][C:30](=[O:31])[NH:32][CH2:33][CH2:34][C:35]([C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)([F:39])[C:36](=[O:38])[N:52]1[CH2:53][CH2:54][N:49]([C:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[N:58]=[CH:57][N:56]=2)[CH2:50][CH2:51]1)([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCC(F)(C(=O)O)c1ccc(Cl)cc1
Reactant: c1ccc2c(N3CCNCC3)ncnc2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(F)(C(=O)N1CCN(c2ncnc3ccccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36 %

Procedure:
PyBrop (562 mg, 1.21 mmol) was added in a single portion to a solution of 4-tert-butoxycarbonylamino-2-(4-chlorophenyl)-2-fluoro-butyric acid (400 mg, 1.21 mmol) and 4-piperazin-1-yl-quinazoline dihydrochloride (346 mg, 1.21 mmol) in DCM (12 mL) cooled in an ice bath. DIEA (0.84 mL, 4.82 mmol) was added and the mixture was allowed to warm to ambient temperature and stirred for 12 hours. The mixture was diluted with DCM and washed with 0.1N HCl. The separated DCM layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was chromatographed (SiO2) using 2% MeOH/DCM followed by 5% MeOH/DCM as eluent to give [3-(4-chlorophenyl)-3-fluoro-4-oxo-4-(4-quinazolin-4-yl-piperazin-1-yl)-butyl]-carbamic acid tert-butyl ester (230 mg). LCMS (APCI+) m/z 528, 530 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:28]([OH:30])=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:28]([OH:30])=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][N:17]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([Br:27])=[CH:25][CH:26]=2)(=[O:20])=[O:19])[CH2:36][C:35]2[CH:38]=[CH:39][C:32]([F:31])=[CH:33][CH:34]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H](CCCCNS(=O)(=O)c1ccc(Br)cc1)NS(=O)(=O)c1ccc(Br)cc1
Reactant: Fc1ccc(CBr)cc1
Product: O=C(O)[C@H](CCCCN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(Br)cc1)NS(=O)(=O)c1ccc(Br)cc1
Yield: 85 %

Procedure:
Nα,Nε-di-(4-bromobenzenesulfonyl)-L-lysine was reacted with 4-fluorobenzyl bromide under the conditions described in example 127 to yield 85% of the desired product.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][C:65]=1[F:72]>ClCCCl>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[C:65]([F:72])[CH:66]=1)#[N:69]
Reactant: N#Cc1ccc(N)c(F)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2F)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 27, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.53 g, 0.92 mmol), was reacted with diisopropylethylamine (0.95 g, 7.4 mmol), diphenylphosphinic chloride (0.87 g, 3.7 mmol), then reacted with 4-amino-3-fluorobenzonitrile (Matrix) (0.13 g, 0.92 mmol) in 1,2-dichloroethane at 70° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-fluoro-phenyl)-amide as a off white solid (Yield 0.14 g, 26%).
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4]2[O:8][C:7]([CH3:9])=[CH:6][C:5]2=[C:10]([CH:13]=O)[C:11]=1[OH:12].[CH:16](B(O)O)=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(NCC1C=CC=CC=1)C1C=CC=CC=1.O>O1CCOCC1>[F:15][C:3]1[C:2]([F:1])=[C:11]2[C:10]([CH:13]=[CH:16][CH:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[O:12]2)=[C:5]2[CH:6]=[C:7]([CH3:9])[O:8][C:4]=12
Reactant: CCCCCC=CB(O)O
Reactant: Cc1cc2c(C=O)c(O)c(F)c(F)c2o1
Agent: c1ccc(CNCc2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCCCCC1C=Cc2c(c(F)c(F)c3oc(C)cc23)O1

Procedure:
4.0 g (18.6 mmol) of 6,7-difluoro-5-hydroxy-2-methylbenzofuran-4-carbaldehyde are stirred for 20 h at 90° C. together with 3.21 g (22.6 mmol) of 1-hepteneboronic acid and 0.72 ml (3.73 mmol) of dibenzylamine in 95 ml of 1,4-dioxane. Water is added to the reaction mixture, which is then extracted with MTBE. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with water and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is firstly purified by column chromatography (SiO2, 1-chlorobutane) and subsequently crystallised from methanol, giving 4,5-difluoro-2-methyl-7-pentyl-7H-furo[3,2-f]chromene as a yellow, crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]([C:15]([C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)=[O:16])=[CH:10][C:9]=1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.Br[CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([O:14][CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:11]([C:15]([C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)=[O:16])=[CH:10][C:9]=1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1
Reactant: Cn1ccnc1C(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1ccnc1C(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1OCC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of Step A in 4 mL DMF was added 0.125 g (0.698 mmol) of 1-bromopinacolone and 0.455 g (1.39 mmol) of Cs2CO3. The reaction mixture was stirred at room temperature for 1 h, then partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic layer was separated, washed with aq. NaHCO3, brine, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0–75% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10]([OH:12])=[O:11].[C:13](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[F:9][C:5]1[CH:4]=[C:3]([S:10]([CH3:13])(=[O:12])=[O:11])[C:2]([F:1])=[CH:7][C:6]=1[F:8]
Reactant: O=C([O-])[O-]
Reactant: O=S(O)c1cc(F)c(F)cc1F
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CS(=O)(=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 60 h
Yield: 98 %

Procedure:
To 2,4,5-trifluoro-benzenesulfinic acid (2.0 g) in DMF (17 mL) was added 4.3 g of potassium carbonate, and the reaction mixture was stirred for 5 minutes before methyl iodide (2.2 mL) was added. The reaction mixture was then stirred at room temperature for 60 hours. After such time, water (30 mL) was poured onto the reaction mixture, and the reaction mixture was extracted with diethylether several times. The combined organic phases were dried with sodium sulfate, and the remaining mixture was distilled to yield the title compound as a light yellow oil (2.1 g).