Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([S:14]([CH3:16])=[O:15])[S:13][C:6]=12>C(O)(=O)C.[Fe]>[CH3:16][S:14]([C:12]1[S:13][C:6]2[C:7](=[N:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]2[CH:17]=[CH:18][C:19]([NH2:21])=[CH:20][C:2]=2[F:1])[CH:11]=1)=[O:15]
Reactant: CS(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: [Fe]
Solvent: CC(=O)O
Product: CS(=O)c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reaction time: 0.08 h
Yield: 77.9 %

Procedure:
To as solution of 233 (400 mg, 1.135 mmol) in acetic acid (10 mL) at 100° C., was added iron powder (317 mg, 5.675 mmol). The reaction mixture was stirred for 5 minutes, filtered through a celite pad and concentrated under reduced pressure. The residue was purified by column chromatography, eluent EtOAc/hexane (4:1), to afford title compound 234 (0.285 g, 69% yield) as a yellow solid. MS (m/z): 323.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.ClCCl.[OH-].[Na+].[F:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH2:17]Br>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[NH2:1][C:2]1[C:7]([O:8][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:15]=2[F:14])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1O
Reactant: Fc1ccc(CBr)c(F)c1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Nc1ncccc1OCc1ccc(F)cc1F
Reaction time: 0.08 h

Procedure:
A mixture of 2-amino-3-hydroxy pyridine (2.66 g, 0.024 mol), dichloromethane (20 ml) and 40% aqueous sodium hydroxide solution (20 ml) was stirred for five minutes, then 2,4-difluorobenzyl bromide (5.00g, 0.024 mol) and Adogen 464 (3 ml) were added and stirring continued for 16 hours. The mixture was diluted with water and extracted with dichloromethane. Drying and evaporation of the organic extracts, and trituration with ether gave the desired product. Yield 2.7 g (48%), m.p. 105°-107 ° C.
Reaction SMILES: [C:1]([NH:9][CH2:10][C@@H:11]([C@@H:19]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:20]([NH:22][NH:23]C(OCC1C=CC=CC=1)=O)=[O:21])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[C:1]([NH:9][CH2:10][C@@H:11]([C@@H:19]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:20]([NH:22][NH2:23])=[O:21])[C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@@H](C(=O)NNC(=O)OCc1ccccc1)[C@H](CNC(=O)c1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)C[C@@H](C(=O)NN)[C@H](CNC(=O)c1ccccc1)C(=O)OC(C)(C)C
Yield: 98.7 %

Procedure:
A solution of 0.81 g of 2(R)-[2-benzamido-1(R)-(tert-butoxycarbonyl)ethyl]-2′-benzyloxycarbonyl-4-methylvalerohydrazide in 10 ml of ethanol was hydrogenated in the presence of 0.080 g of 10% palladium-on-carbon for 4 hours. The catalyst was removed by filtration and evaporation gave 0.59 g of 2(R)-[2-benzamido-1(R)-(tert-butoxycarbonyl)ethyl]-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@@H:10]([OH:15])[CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:21]1C(=O)C2[CH:24](C3CC2C=C3)[C:22]1=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.C(N)C.CN1CCOCC1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@@H:10]([OH:15])[CH2:11][C:12]([NH:21][CH2:22][CH3:24])=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CC(=O)O
Reactant: O=C1C2C3C=CC(C3)C2C(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCNC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
275 mg (1 mmole) of 4(S)-t-butoxycarbonylamino-3(S)-hydroxy-6-methylheptanoic acid and 197 mg (1.1 mmole) of N-hydroxy-5-norbornene-2,3-dicarboximide were dissolved in 10 ml of methylene chloride and ice-cooled. To this solution were added 227 mg (1.1 mmole) of dicyclohexylcarbodiimide, and the mixture was stirred for 1 hour whilst ice-cooling and for a further 2 hours at room temperature. 90 mg (1.1 mmole) of ethylamine hydrochloride and 111 mg (1.1 mmole) of N-methylmorpholine were then added and the reaction mixture was stirred overnight at room temperature. The precipitated dicyclohexylurea was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. A 10% w/v aqueous solution of citric acid was added to the resulting residue, and the precipitated oily substance was extracted with ethyl acetate. The organic extract was washed with, in turn, a 10% w/v aqueous solution of citric acid, water, a 5% w/v aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. Diethyl ether was added to the oily residue to remove insoluble matter, and the filtrate was concentrated by evaporation under reduced pressure. Hexane was added to the resulting oily residue, to solidify it, and the solid was reprecipitated from a 2:1 by volume mixture of hexane and diethyl ether and filtered to give the title compound as a white powdery solid melting at 103°-107° C., [α]23 -43.6° (C=0.5, methanol).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.[C:12]1(C)[CH:17]=CC(S([O-])(=O)=O)=C[CH:13]=1.[NH+]1C=CC=CC=1>CC(C)=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][O:10][C:12]([CH3:17])([CH3:13])[O:11]2)=[CH:6][N:7]=1
Reactant: OCC(O)c1ccc(Br)nc1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC1(C)OCC(c2ccc(Br)nc2)O1
Yield: 267.4 %

Procedure:
To a solution of 1-(6-bromopyridin-3-yl)ethane-1,2-diol (4.20 g) in acetone (80 mL) was added pyridinium p-toluenesulfonate (1.50 g), and the mixture was stirred with heating under reflux for 3 hr. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give the title compound (4.12 g, yield 72%) as a pale-yellow solid. MS: 260 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:25])[O:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)([O-])=O.C([O-])=O.[NH4+]>CO.C1COCC1.[Zn]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:25])[O:17][CH2:18][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=C(Nc1cc(-c2cccs2)ccc1[N+](=O)[O-])OCC1CCCCC1
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(-c2cccs2)cc1NC(=O)OCC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.8 %

Procedure:
To a stirred solution of cyclohexylmethyl (2-nitro-5-(thiophen-2-yl)phenyl)carbamate (0.09 g, 0.25 mmol, 1.0 equiv.) in methanol (5 mL) and THF (5 mL) were added Zn (0.08 mg, 1.25 mmol, 5.0 equiv.) and HCOONH4 (0.13 mmol, 2.0 mmol, 8.0 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 4 h then filtered through celite and concentrated under reduced pressure. The crude residue was diluted with ethyl acetate, washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (silica gel, 30% EtOAc/hexanes) to afford cyclohexylmethyl (2-amino-5-(thiophen-2-yl)phenyl)carbamate (0.08 g, 100% yield). ESI+ MS: m/z 331 ([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 8.58 (bs, 1H), 7.52 (bs, 1H), 7.33 (d, J=4.5 Hz, 1H), 7.22-7.14 (m, 2H), 7.03 (dd, J=3.5, 5.0 Hz, 1H), 6.72 (d, J=8.0 Hz, 1H), 5.11 (s, 2H), 3.89 (d, J=6.5 Hz, 2H), 1.80-1.38 (m, 6H), 1.25-1.03 (m, 3H), 1.03-0.92 (m, 2H).
Reaction SMILES: ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C.[CH3:22][S:23]([CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35]C(C)(C)C)=O)[CH2:29][CH2:28]1)(=[O:25])=[O:24].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH2:54][C@@H:55]([CH2:69][C:70]1[CH:75]=[C:74]([F:76])[CH:73]=[C:72]([F:77])[CH:71]=1)[C@H:56]([OH:68])[CH2:57][NH:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([CH2:66][CH3:67])[CH:61]=1.Cl>C(Cl)Cl.CO.C(OCC)C>[F:76][C:74]1[CH:75]=[C:70]([CH:71]=[C:72]([F:77])[CH:73]=1)[CH2:69][C@H:55]([NH:54][C:33]([N:30]1[CH2:29][CH2:28][CH:27]([CH2:26][S:23]([CH3:22])(=[O:24])=[O:25])[CH2:32][CH2:31]1)=[O:35])[C@H:56]([OH:68])[CH2:57][NH:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([CH2:66][CH3:67])[CH:61]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CS(C)(=O)=O)CC1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)N2CCC(CS(C)(=O)=O)CC2)c1
Temperature: 0 °C
Yield: 7.2 %

Procedure:
To an ice-cold, stirred solution of triphosgene (108 mg, 0.36 mmol) and diisopropylethylamine (0.6 mL, 3.3 mmol) in methylene chloride (2.0 mL) was added amino sulfone from step 4 (210 mg, 0.98 mmol) in methylene chloride (3.5 mL) dropwise. After 5 min a solution of dihydrochloride of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (401 mg, 0.98 mmol) was added and the reaction mixture was warmed until the solution became homogeneous. The reaction mixture was diluted with methylene chloride, washed with 1 N hydrochloric acid (25 mL), saturated sodium bicarbonate (25 mL), and saturated sodium chloride, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 15:85 methanol/chloroform) provided a clear solid. The solid was dissolved in methanol (1 mL), and treated with hydrochloric acid (0.3 mL of a 1.0 M solution in diethyl ether, 0.3 mmol). The resulting precipitate was collected by filtration to provide the title compound (38 mg): mp 130–134° C.; APCI MS m/z 538 [M+H]+.
Reaction SMILES: [C:1](=[O:43])(SCC)[O:2][CH2:3][O:4][C:5](=[O:39])[CH2:6][CH2:7][C:8](=[O:38])[NH:9][C:10]([CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].S(Cl)([Cl:47])(=O)=O>>[Cl:47][C:1]([O:2][CH2:3][O:4][C:5](=[O:39])[CH2:6][CH2:7][C:8](=[O:38])[NH:9][C:10]([CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:43]
Reactant: CCSC(=O)OCOC(=O)CCC(=O)NC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)CCC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)Cl
Product: CC(C)(C)OC(=O)CCC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)NC(=O)CCC(=O)OCOC(=O)Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of carbonothioate 74 (351 mg, 0.55 mmol) in ice-cold CH2Cl2 (3 mL) was added sulfuryl chloride (67 μL, 0.83 mmol) and the mixture was stirred at 0° C. for 3 h, after which the mixture was concentrated to dryness, providing chloroformate 75 as a colorless gum (334 mg, quant.) which was used directly in the next step: 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 27H), 1.94-1.98 (m, 6H), 2.21-2.24 (m, 6H), 2.46 (t, J=6.6 Hz, 2H), 2.74 (t, J=6.6 Hz, 2H), 5.83 (s, 2H), 6.15 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[CH3:22][C:23]1([CH3:32])[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25](=O)[CH2:24]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:25]2[CH2:26][C:27]([CH3:30])([CH3:29])[CH2:28][C:23]([CH3:32])([CH3:22])[CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1ccc(C(=O)c2ccc(O)cc2)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
To a stirred suspension of zinc powder (0.76 g, 11.54 mmol) in THF (30 mL) was slowly added TiCl4 (0.64 mL, 5.77 mmol) via syringe at room temperature under a nitrogen atmosphere. The mixture was heated at reflux for 2 h. A solution of methyl 3-{4-[(4-hydroxyphenyl)carbonyl]phenyl}propanoate (168) (0.41 g, 1.44 mmol) and 3,3,5,5-tetramethyl cyclohexanone (0.68 g, 4.33 mmol) in THF (10 mL) was added to the mixture. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 2 h. The reaction mixture was allowed to cool to room temperature. To the reaction mixture was slowly added 10% aqueous K2CO3 (30 mL). The reaction mixture was filtered through a pad of Celite and the pad washed with EtOAc (100 mL). The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was further extracted with EtOAc (25 mL). The combined organic phase washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as yellow oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 20% EtOAc:hexanes to give light brown oil, which upon adding hexanes solidified. The solid was triturated with hot hexanes to afford 0.40 g (68%) of compound 169 as white solid. mp 129-130° C. 1H NMR (400 MHz, CDCl3): δ 0.92 (s, 12H), 1.27 (s, 2H), 1.94 (s, 2H), 1.95 (s, 2H), 2.61 (t, J=7.5 Hz, 2H), 2.91 (t, J=7.5 Hz, 2H), 3.66 (s, 3H), 4.57 (s, 1H), 6.73 (d, J=8.5 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 7.04-7.10 (m, 4H). LCMS (ESI): m/z 429 (M+Na)+, m/z 405 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl-].[CH3:11]N(C=NC=[N+](C)C)C>O1CCOCC1>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][CH:11]=[N:1][C:2]=2[CH:7]=1
Reactant: CN(C)C=NC=[N+](C)C
Reactant: Cc1ccc(O)c(N)c1
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cc1ccc2ocnc2c1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
Combine 2-amino-4-methyl-phenol (1.0 g, 8.12 mmol), [(dimethylaminomethylene-aminomethylene)dimethylammonium chloride (Gold's reagent) (1.6 g, 9.91 mmol), anhydrous 1,4-dioxane (25 mL) and reflux for 17 h. Cool the reaction mixture to ambient temperature, evaporate the solvent and purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to obtain the desired intermediate as a yellow oil (0.7 g, 65%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](Cl)(C)C>CO>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)c1cc(C)ccc1Br

Procedure:
A solution of 2-bromo-5-methylbenzoic acid (10 g) in trimethylsilyl chloride (30 ml) and methanol (100 ml) was stirred at room temperature overnight and evaporated. The residue was partitioned between ethyl acetate and sodium bicarbonate solution, dried (MgSO4) and evaporated. Yield 10.1 g.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH:7]=[CH:8][C:9]1[CH2:16][C@H:15]2[C@H:11]([CH2:12][C@@H:13]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[C@H:14]2/[CH:17]=[CH:18]/[C:19](=[O:27])[C:20]([F:26])([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:10]=1)=[O:4].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]([CH2:5][CH2:6][CH:7]=[CH:8][C:9]1[CH2:16][C@H:15]2[C@H:11]([CH2:12][C@@H:13]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[C@H:14]2/[CH:17]=[CH:18]/[CH:19]([OH:27])[C:20]([F:26])([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:10]=1)=[O:4]
Reactant: CCCCC(F)(F)C(=O)/C=C/[C@H]1[C@H]2CC(C=CCCC(=O)OC)=C[C@H]2C[C@H]1OC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCC(F)(F)C(O)/C=C/[C@H]1[C@H]2CC(C=CCCC(=O)OC)=C[C@H]2C[C@H]1OC1CCCCO1
Reaction time: 0.5 h

Procedure:
(1S,5S,6S,7R)-3-[4-Methoxycarbonyl-1(EZ)-butenyl]-6-[4,4-difluoro-3-oxo-(E )-1-octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]oct-2-ene (16) (0.196 g) was dissolved in methanol. To the solution, sodium borohydride (0.015 g) was added at 0° C., and the mixture was stirred for 30 minutes. After a usual work-up (1S,5S,6S,7R)-3-[4-methoxycarbonyl-1(EZ)-butenyl]-6-[4, 4-difluoro-3-(RS)hydroxy-(E)-1--octenyl]-7-tetrahydropyranyloxy-bicyclo[3.3.0]oct-2-ene (17) was obtained as a colorless oily product. Yield: 0.184 g (93%)
Reaction SMILES: [C:1]([NH:3][C:4](=[NH:7])[S:5][CH3:6])#[N:2].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.N1CCCC1>>[NH2:2][C:1]1[C:17]2[CH2:16][CH:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[Cl:8])[CH2:20][CH2:19][C:18]=2[N:7]=[C:4]([S:5][CH3:6])[N:3]=1
Reactant: CSC(=N)NC#N
Reactant: O=C1CCC(c2ccccc2Cl)CC1
Solvent: C1CCNC1
Product: CSc1nc(N)c2c(n1)CCC(c1ccccc1Cl)C2
Temperature: 150 °C

Procedure:
A suspension of 1.2 grams of (0.010 mole) of N-cyano-S-methylisothiourea [prepared in the manner disclosed by R. W. Turner; Synthesis, 332 (1975)], 2.1 grams (0.010 mole) of 4-(2-chlorophenyl)cyclohexanone and 0.4 gram (0.005 mole) of pyrrolidine is placed in a glass tube, which is then sealed. The sealed tube is heated at 150° C. for about seven hours. After this time, the sealed tube is cooled in an ice-bath and opened. The reaction mixture is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography using silica gel, yielding 4-amino-2-methylthio-6-(2-chlorophenyl)-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: Cl[C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH3:12][NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)=[O:15].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)CCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:6][C:5]1[C:4]([O:10][CH3:11])=[CH:3][C:2]([C:19]2[CH:20]=[CH:21][C:16]([C:14]([NH:13][CH3:12])=[O:15])=[CH:17][CH:18]=2)=[C:8]([CH3:9])[CH:7]=1
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Reactant: COc1cc(Cl)c(C)cc1N
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCO
Product: CNC(=O)c1ccc(-c2cc(OC)c(N)cc2C)cc1
Temperature: 130 °C

Procedure:
The mixture of 4-chloro-2-methoxy-5-methylaniline (2.0 g, 11.7 mmol), 4-(methylcarbamoyl)phenylboronic acid (2.08 g, 11.7 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.20 g, 2.9 mmol), Pd2(dba)3 (1.1 g, 1.2 mmol), and K3PO4 (7.4 g, 34.9 mmol) in 80 mL of n-butanol is degassed and heated at 130° C. overnight. The reaction mixture is filtered through a pad of celite, and concentrated in vacuo. The crude product mixture is partitioned between EtOAc and brine, the collected organic extracts are dried (Na2SO4), concentrated, and purified by silica gel chromatography (EtOAc/Hexanes:1/4) to afford 4′-Amino-5′-methoxy-N,2′-dimethylbiphenyl-4-carboxamide; ESMS m/z 271.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:15])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH3:13])[C:7]2=[O:14].Cl.[CH3:17][C:18]1([NH2:21])[CH2:20][CH2:19]1.C(N(C(C)C)C(C)C)C>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[C:3]([F:15])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:21][C:18]1([CH3:17])[CH2:20][CH2:19]1)[N:8]([CH3:13])[C:7]2=[O:14]
Reactant: Cn1c(Cl)nc2c(Br)c(F)ccc2c1=O
Reactant: CC1(N)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cn1c(NC2(C)CC2)nc2c(Br)c(F)ccc2c1=O
Yield: 43.8 %

Procedure:
A brown solution of 8-bromo-2-chloro-7-fluoro-3-methylquinazolin-4(3H)-one (720, 180 mg, 0.617 mmol), 1-methylcyclopropanamine hydrochloride (Small Molecules, Inc., 133 mg, 1.235 mmol), and N-ethyl-N-isopropylpropan-2-amine (237 μL, 1.358 mmol) in DMSO (6.2 mL) was stirred at 80° C. for 1 h when product was observed via LCMS. The reaction mixture was diluted with EtOAc (100 mL), added to a separatory funnel, and washed with saturated aqueous NaHCO3 (2×75 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 0-100% EtOAc in hexanes to give 8-bromo-7-fluoro-3-methyl-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one (510a, 88 mg, 0.270 mmol, 43% yield) as a brown oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.80-0.87 (m, 2H) 0.87-0.93 (m, 2H) 1.61 (s, 3H) 3.42 (s, 3H) 5.12 (br. s., 1H) 6.92 (t, J=8.51 Hz, 1H) 8.06 (dd, J=8.80, 6.06 Hz, 1H). 19F NMR (376 MHz, CDCl3) δ ppm −96.48 (s, 1F). MS (ESI, pos. ion) m/z: 326.0/328.0 (M+1).
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:20])([F:19])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl>[Br:1][C:16]1[CH:17]=[CH:18][N:14]([S:11]([C:8]2[CH:7]=[CH:6][C:5]([C:4]([F:3])([F:19])[F:20])=[CH:10][CH:9]=2)(=[O:13])=[O:12])[CH:15]=1
Reactant: BrBr
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)n1cccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)n1ccc(Br)c1
Temperature: 100 °C
Yield: 75.6 %

Procedure:
Bromine (4.12 mL, 80.1 mmol) was added to a solution of 1-(4-(trifluoromethyl)phenylsulfonyl)-1H-pyrrole (111) (21 g, 76.2 mmol) in acetic acid (254 mL) and the resulting solution was heated to 100° C. for 1 h. The mixture was diluted with CH2Cl2 and poured slowly into ice cold aqueous sodium hydroxide (3 N). The solution was adjusted to pH 7 with aqueous sodium hydroxide (3 N), extracted with CH2Cl2. The organic phase was separated, dried (Na2SO4), filtered and concentrated under vacuum and purified on a silica gel column (eluant hexane/EtOAc, 4/1, v/v) to give compound 112 (20.4 g, 57.6 mmol, 75%). MS (ESI) 354.0 (M+H).
Reaction SMILES: [C:1]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=O)[CH2:20][C:19]2=[O:31])[CH2:14][CH2:13]1)=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.ClCCl>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([CH:15]2[CH2:16][CH2:17][N:12]([C:10]([O:9][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:11])[CH2:13][CH2:14]2)[C:19](=[O:31])[CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCN(C(=O)OC(=O)c3ccccc3)CC2)C(=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C(=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.8 %

Procedure:
tert-Butyl 4-{1-[(benzoyloxy)carbonyl]piperidin-4-yl}-3-oxopiperazin-1-carboxylate (0.42 g) obtained in Example 12b) was dissolved in trifluoroacetic acid (1 mL) and dichloromethane (1 mL), and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated, toluene was added to the residue and it was concentrated again under reduced pressure. The residue was dissolved in dichloromethane (15 mL) and formalin (37%; 0.5 mL) was added. After the reaction mixture was stirred at room temperature for 2 hours, sodium triacetoxyborohydride (0.53 g) was added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was washed with an aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.38 g, quantitative) as a light yellow oil.