Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([OH:18])=[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]1=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N+](=[CH2:27])=[N-]>ClCCl.CO.CCOCC>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:27])=[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]1=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=[N+]=[N-]
Reactant: CCCCCCn1c(=O)c(C(=O)OCC)c(O)c2cc(C)ccc21
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: CCCCCCn1c(=O)c(C(=O)OCC)c(OC)c2cc(C)ccc21

Procedure:
Then a solution of the 1-hexyl-3-ethoxycarbonyl-4-hydroxy-6-methyl-2(1H)-quinolinone (12.4 g) in dichloromethane (50 ml ) and methanol (10 ml) was treated with excess diazomethane in ether for 10 mins. This solution was then evaporated. The crude methylation product upon chromatography on silica gel yielded 1-hexyl-3-ethoxycarbonyl-4-methoxy-6-methyl-2(1H)-quinolinone (11.5 g). The 1-hexyl-3-ethoxycarbonyl-4-methoxy-6-methyl-2(1H)-quinolinone (7.13 g) in dry toluene (80 ml) was cooled to -78° C. and then a 1M solution of di-isobutyl aluminum hydride (30 ml) was added dropwise in 10 min. After 2.5 hours of stirring at -78° C. the reaction mixture was worked up by stirring with aqueous ammonium chloride/1N hydrochloric acid which was then followed by extraction with methylene chloride. The crude reduction product was chromatographed on silica gel and then crystallized from ethyl acetate/hexane to give 1-hexyl- 3-formyl-4-methoxy-6-methyl-2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS(CI): m/e 302 (M+): NMR (CDCl3): δ2.42 (s, 3H, Ar-CH3), 4.10 (s, 3H, OCH3), 10.50 (s, 1H, CHO).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][N:21]3[C:24](=[O:26])[CH3:25])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCCC(=O)C1)C1C=CC=CC=1.C(N1C2C(=CC=C(N)C=2)CC1)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O.[C:72](Cl)(=[O:81])[CH:73]=[CH:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1>ClCCCl>[C:24]([N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([N:14]([CH:10]3[CH2:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9]3)[C:72](=[O:81])/[CH:73]=[CH:74]/[C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)[CH:23]=2)[CH2:19][CH2:20]1)(=[O:26])[CH3:25]
Reactant: CC(=O)N1CCc2ccc(NC3CCCN(Cc4ccccc4)C3)cc21
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: CC(=O)N1CCc2ccc(N)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C1CCCN(Cc2ccccc2)C1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(=O)N1CCc2ccc(N(C(=O)/C=C/c3ccccc3)C3CCCN(Cc4ccccc4)C3)cc21
Yield: 99 %

Procedure:
1-[6-(1-Benzyl-piperidin-3-ylamino)-2,3-dihydro-indol-1-yl]-ethanone. The desired intermediate (116 mg, 30%) was prepared as in Example 39, Step A, employing 1-benzyl-3-piperidone (510 mg, 4.4 mmol), 1-acetyl-6-aminoindoline (200 mg, 1 mmol), Na(OAc)3BH (910 mg, 4.3 mmol), and AcOH (340 μL, 5.4 mmol) in 1,2-dichloroethane (20 mL). Step B. The above intermediate (0.10 g, 0.29 mmol) was then reacted with cinnamoyl chloride (62 mg, 0.37 mmol) as in Example 2, Step C to provide 145 mg (99%) of the desired product. 1H NMR (500 MHz, CDCl3): 8.04 (s, 1H), 7.62 (d, J=15.5 Hz, 1H), 7.30-7.18 (m, 10H), 7.15 (d, J=7.8 Hz, 1H), 6.74 (dd, J=7.3, 1.4 Hz, 1H), 6.16 (d, J=15.5 Hz, 1H), 4.79-4.68 (m, 1H), 4.18-4.07 (m, 2H), 3.30-3.15 (m, 2H), 2.98-2.85 (m, 2H), 2.26-2.23 (m, 2H), 2.21 (s, 3H), 2.15-2.01 (m, 2H), 1.93-1.75 (m, 2H), 1.60-1.35 (m, 3H). MS: exact mass calculated for C31H33N3O2, 479.26; m/z found, 480.2 [M+H]+.
Reaction SMILES: B(Br)(Br)Br.S(C)C.C[O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13]2>ClCCCl>[OH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13]2
Reactant: COc1ccc2c(c1)CC(=O)N2
Agent: BrB(Br)Br
Solvent: ClCCCl
Solvent: CSC
Product: O=C1Cc2cc(O)ccc2N1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
An oven-dried flask was charged with BBr3.SMe2 (2.80 g, 9.20 mmol) and 1,2-dichloroethane (15 mL). 5-Methoxyindolin-2-one (0.30 g, 1.84 mmol) was then added and the mixture was heated to reflux for 18 hours. The reaction was then cooled to room temperature and quenched with MeOH (1.0 mL). The mixture was then extracted into EtOAc washing with brine (3×). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo; the resulting residue was then purified by column chromatography (silica gel, 94:6 to 92:8, CH2Cl2/MeOH) to give 144 mg, 53% of a beige powder. MS ESI 149.9 [M+H]+, calcd for [C8H7NO2+H]+ 150.06
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[C:21]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]([CH3:32])[NH:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=[C:18]([O:33][CH3:34])[N:17]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:22]([C:21]5[C:16]([O:15][CH3:14])=[N:17][C:18]([O:33][CH3:34])=[CH:19][CH:20]=5)[CH:23]=4)[CH:28]3[CH3:32])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: COc1ccc(-c2ccc3c(c2)CCNC3C)c(OC)n1
Product: COc1ccc(-c2ccc3c(c2)CCN(C(=O)c2cc4ncc(Br)cn4n2)C3C)c(OC)n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2,6-Dimethoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15](OS(C(F)(F)F)(=O)=O)=[CH:16][CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]([CH3:32])([CH3:31])[C:29]#[CH:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([C:30]#[C:29][C:28]([CH3:32])([CH3:31])[CH3:27])=[CH:16][CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(OS(=O)(=O)C(F)(F)F)c2CC1
Product: CC(C)(C)C#Cc1cccc2c1CCN(C(=O)OC(C)(C)C)CC2
Yield: 71.4 %

Procedure:
Use a method similar to the General Procedure 3 to couple 3-tert-butoxycarbonyl-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.5 g, 1.3 mmol) with 3,3-dimethyl-1-butyne (0.311 mL, 2.5 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1) to give 3-tert-butoxycarbonyl-6-(3,3-dimethyl-but-1-ynyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (304 mg, 74%).
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][CH2:7][C@H:3]1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[ClH:43].[NH:44]1[CH2:49][CH2:48][CH:47]([CH2:50][CH2:51][O:52][C:53]2[CH:58]=[CH:57][C:56]([C:59]3[C:60]4[CH:69]=[CH:68][N:67]([CH2:70][CH:71]5[CH2:75][CH2:74][CH2:73][O:72]5)[C:61]=4[N:62]=[C:63]([C:65]#[N:66])[N:64]=3)=[CH:55][C:54]=2[C:76]([F:79])([F:78])[F:77])[CH2:46][CH2:45]1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O.O>[ClH:43].[CH3:1][N:2]1[CH2:9][CH2:8][CH2:7][C@H:3]1[C:4]([N:44]1[CH2:45][CH2:46][CH:47]([CH2:50][CH2:51][O:52][C:53]2[CH:58]=[CH:57][C:56]([C:59]3[C:60]4[CH:69]=[CH:68][N:67]([CH2:70][CH:71]5[CH2:75][CH2:74][CH2:73][O:72]5)[C:61]=4[N:62]=[C:63]([C:65]#[N:66])[N:64]=3)=[CH:55][C:54]=2[C:76]([F:77])([F:78])[F:79])[CH2:48][CH2:49]1)=[O:6]
Reactant: N#Cc1nc(-c2ccc(OCCC3CCNCC3)c(C(F)(F)F)c2)c2ccn(CC3CCCO3)c2n1
Reactant: CN1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCC[C@H]1C(=O)N1CCC(CCOc2ccc(-c3nc(C#N)nc4c3ccn4CC3CCCO3)cc2C(F)(F)F)CC1
Reaction time: 8 h
Yield: 79.7 %

Procedure:
1-Methyl-L-proline (33 mg), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (85 mg), and N,N-diisopropylethylamine (64 μL) were added to a solution of 4-{4-[2-(piperidin-4-yl)ethoxy]-3-(trifluoromethyl)phenyl}-7-(tetrahydrofuran-2-yl methyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile monohydrochloride (80 mg) in DMF (1.6 mL) at room temperature, and the mixture was stirred at the same temperature overnight. After the reaction mixture was diluted with EtOAc, a saturated aqueous NaHCO3 solution and water were added thereto, then extraction thereof was performed using EtOAc, and the extract was washed with saturated brine. The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (Hex:CHCl3=50:50 to 0:100). The obtained product was dissolved in EtOAc (1 mL), then a 4 M solution of hydrogen chloride in EtOAc (31 μL) was added thereto at room temperature, and the mixture was stirred at the same temperature for 1 hour. The precipitate was collected by filtration, whereby 4-[4-{2-[1-(1-methyl-L-prolyl)piperidin-4-yl]ethoxy}-3-(trifluoromethyl)phenyl]-7-(tetrahydrofuran-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile monohydrochloride (77 mg) was obtained as a pale yellow solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([C:6]([NH2:9])([CH3:8])[CH3:7])[CH2:2]1.[CH:10]1([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20](F)[C:21]=3[O:23][CH3:24])[C:16](=[O:26])[C:15]3[C:27]([OH:32])=[C:28]([C:30]#[N:31])[S:29][C:14]2=3)[CH2:12][CH2:11]1.OC1C2C(=O)C3C(=C(OC)C=CC=3)NC=2SC=1C#N>>[NH2:9][C:6]([C@@H:3]1[CH2:4][CH2:5][N:1]([C:20]2[C:21]([O:23][CH3:24])=[C:22]3[C:17]([C:16](=[O:26])[C:15]4[C:27]([OH:32])=[C:28]([C:30]#[N:31])[S:29][C:14]=4[N:13]3[CH:10]3[CH2:11][CH2:12]3)=[CH:18][CH:19]=2)[CH2:2]1)([CH3:8])[CH3:7]
Reactant: CC(C)(N)[C@@H]1CCNC1
Reactant: COc1c(F)ccc2c(=O)c3c(O)c(C#N)sc3n(C3CC3)c12
Agent: COc1cccc2c(=O)c3c(O)c(C#N)sc3[nH]c12
Product: COc1c(N2CC[C@@H](C(C)(C)N)C2)ccc2c(=O)c3c(O)c(C#N)sc3n(C3CC3)c12

Procedure:
The title compound is prepared from (R)-2-(pyrrolidin-3-yl)propan-2-amine (Fedji, et al., 1994) and 9-cyclopropyl-7-fluoro-3-hydroxyl-8-methoxy-4-oxo-4,9-dihydrothieno[2,3-b]quinoline-2-carbonitrile using the method described above for the preparation of 9-cyclopropyl-6-fluoro-7-((R)-3-(S)-1-(2-fluoroethylamino)ethyl)pyrrolidin-1-yl)-3-hydroxyl-8-methoxy-4-oxo-4,9-dihydrothieno[2,3-b]quinoline-2-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[N:38]1([C:46](=[S:48])[NH2:47])[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:48][C:46]([N:38]3[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]3)=[N:47][C:9]=2[C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NC(=S)N1CCS(=O)(=O)CC1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Agent: O=C1CCC(=O)N1Br
Product: O=S1(=O)CCN(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Yield: 90 %

Procedure:
Following a procedure analogous to Intermediate 6 using N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (1.5 g, 3.40 mmol), NBS (0.60 g, 3.40 mmol) and 4-thiomorpholinecarbothioamide 1,1-dioxide (0.80 g, 4.12 mmol) the title compound of Step A was obtained (1.88 g, 90% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.94 (br. s., 1H), 8.34 (d, J=5.1 Hz, 1H), 7.59-7.78 (m, 1H), 7.37-7.52 (m, 2H), 7.32 (t, J=7.7 Hz, 1H), 7.25 (t, J=9.1 Hz, 2H), 6.55 (d, J=4.9 Hz, 1H), 4.04 (br. s., 4H), 3.32 (br. s., 4H). m/z (ES+): 617 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH2:7][N:8]([CH2:18][CH3:19])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[CH3:22][S:23]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][N:8]([CH2:18][CH3:19])[CH2:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:21][CH:20]=2)=[CH:12][CH:13]=1)(=[O:25])=[O:24]
Reactant: CCN(CCc1ccc(N)cc1)CCc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Product: CCN(CCc1ccc(NS(C)(=O)=O)cc1)CCc1ccc(NS(C)(=O)=O)cc1

Procedure:
N,N-Bis-(4-aminophenethyl)ethylamine (0.3 g) was acylated with methanesulphonyl chloride in a similar fashion to Example 19(C) to produce the title compound as a foam, yield 0.12 g, m.p. <60°.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:25]([C@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.O.C(OCC)(=O)C>[Br:2][C:1]([Br:5])=[CH:25][C@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C=C(Br)Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
Carbon tetrabromide (49.2 g, 0.15 mol) in methylene chloride (150 mL) was added at 0° C. to a stirred solution of triphenyl phosphine (78.2 g, 0.30 mol) in methylene chloride (600 mL) under nitrogen. The solution was stirred at 0° C. for 1 hr. and (R)-t-butyl 2-formyl-1-pyrrolidinecarboxylate (21.9 g, 0.10 mol) was added. After 30 min. a solution of sodium carbonate (75 g, 0.75 mol) in water (300 mL) was added. The phases were separated and the aqueous phase was reextracted with methylene chloride (200 mL). The organic phase was washed with water (40 mL), and the majority of solvent was removed under reduced pressure leaving the material in a minimum of methylene chloride. Ethyl acetate (500 mL) was added and the resulting precipitate of triphenylphosphine oxide was filtered off. The mother liquors were evaporated and filtered repeatedly to remove additional triphenylphosphine oxide. The residual solid in ethyl acetate was then concentrated and applied to a silica gel column. Elution with ethyl acetate:Skellysolve B (1:10) gave 31.6 g (91%) of product. This was crystallized from petroleum ether to give 25.8 g of product, m.p. 64°-67° C. The analytical sample was recrystallized from ethyl acetate:Skellysolve B. [α]D -21° (c 0.81, MeOH).
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[Br:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[N:17]\[S@@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])=[CH:12][CH:11]=1>C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C@H:16]([NH:17][S@@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[C:2]([F:4])([F:3])[F:1])=[CH:14][CH:15]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)[S@@](=O)/N=C\c1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CC(C)(C)[S@@](=O)N[C@@H](c1ccc(Br)cc1)C(F)(F)F
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
Add neat (trifluoromethyl)trimethylsilane (109 mL, 0.74 mol) at 0° C. to a stirred solution of tetrabutylammonium acetate (88 g, 0.29 mol) and (N—Z)—N-[(4-bromophenyl)methylene]-(R)-2-methyl-propane-2-sulfinamide (85 g, 0.29 mol) in DMF (1.2 L) at 0° C. Stir the mixture at 0-5° C. for 90 minutes. Add saturated aqueous ammonium chloride solution (1.2 L) and extract with EtOAc (4×400 mL). Combine the organic extracts and sequentially wash with water then brine (2×1 L); dry over magnesium sulphate; filter; and concentrate the filtrate under reduced pressure. Triturate the residue with hexane (200 mL) for 10 minutes; filter; and dry the filtrate under vacuum to afford the title compound as a yellow solid (81 g, 76% yield, >98 de). MS (m/z): 358 (M+1).
Reaction SMILES: C[C:2]12[CH2:13][CH2:12][C:8]3([CH2:9][CH2:10][CH2:11]1)[C:3]2(C)[CH2:4][CH2:5][CH:6]=[C:7]3C.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)C.C(OO)(=O)C>O.ClCCl>[CH3:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2][CH2:11][CH2:10][CH2:9][CH2:8][CH2:12][CH3:13]
Reactant: CC1=CCCC2(C)C3(C)CCCC12CC3
Agent: CC(=O)OO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CCCCC=CCCCCCC
Reaction time: 2 h

Procedure:
A mixture of 20.4 g (0.1 mole) of 1,2,6-trimethyltricyclo[5,3,2,02,7 ]dodeca-5-ene and 17 g of sodium carbonate was added to 100 ml of dichloromethane, and the materils were mixed and stirred while keeping the temperature at 0° to 5°C. Then, 20.8 g (0.11 mole) of an acetic acid solution containing 40% peracetic acid was added dropwise thereto over a period of 2 hours at that temperature. The materials were stirred at that temperature for 2 hours, and further stirred at room temperature for 3 additional hours. Subsequently, 200 ml of water was added thereto, and the resulting solution was extracted twice with dichloromethane. The extract was washed with an aqueous saturated sodium chloride solution until the solution became neutral, and then dried with anhydrous sodium sulfate. Dichloromethane was then recovered by distillation, and the residue was distilled in vacuum, whereby 21 g of the fraction of Compound (II) (85°-90°C/0.03 mmHg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:16]O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:16])=[O:10])=[CH:6][CH:7]=1
Reactant: CO
Reactant: Nc1ccc(CC(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(N)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
To a solution of 2-(4-aminophenyl)acetic acid (B−1) (10 g, 66.16 mmol) in methanol (50 mL) was added dropwise SOCl2 (5 mL). The mixture was stirred at 60° C. for 6 h. After evaporated the solvent, the residue was recrystallized with Et2O to afford the product (10.9 g, 99%) as a yellow solid. LC-MS: (M+H)+=166;
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1.[N+:38]([CH2:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])([O-:40])=[O:39].[NH4+].[Cl-]>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].C(OCC)(=O)C.COCCOC>[CH3:47][O:46][C:44](=[O:45])[CH2:43][CH2:42][CH:41]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[N+:38]([O-:40])=[O:39]
Reactant: COc1ccc(Br)cc1
Reactant: COC(=O)CCC[N+](=O)[O-]
Agent: [Pd]
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)CCC(c1ccc(OC)cc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 89.5 %

Procedure:
As described by Buchwald et al. (J. Org. Chem. 2002, 106): in a flask was added successively: 187 mg (0.198 mmol) Pd2 dba3, 247 mg (0.791 mmol) 2-(Di-t-butylphosphino)-2′-methybiphenyl, and 1.555 g (4.747 mmol) cesium carbonate. The mixture was put under argon and 740 mg (3.956 mmol) 4-bromoanisole, 15 ml of DME and finally 600 mg (3.956 mmol) of methyl 4-nitrobutyrate were successively added. The mixture was stirred vigorously for 1 minute at room temperature and the flask was placed in a preheated oil bath at 50° C. and stirred at this temperature overnight. The reaction mixture was cooled to room temperature, and a saturated NH4Cl solution and ethyl acetate were added. Aqueous phase was extracted 3 times with ethyl acetate and combined organic phases were washed with brine, and concentrated in vacuo. The crude product was purified with flash column chromatography on silica gel (Eluent: heptane/ethyl acetate 0 to 20%) to provide 897 mg (90%) of the title compound as a orange oil.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:7]=1[CH:8]=O.CCOCC>FC(F)(F)C(O)=O>[CH3:14][C:11]1[CH:12]=[CH:13][C:6]2[O:5][C:4]([CH:3]=[O:2])=[CH:8][C:7]=2[CH:10]=1
Reactant: COC(COc1ccc(C)cc1C=O)OC
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2oc(C=O)cc2c1
Yield: 68.8 %

Procedure:
154 mg (0.69 mmol) of 2-(2,2-dimethoxy-ethoxy)-5-methyl-benzaldehyde were dissolved in trifluoroacetic acid and the reaction mixture was heated to reflux for 15 min. After cooling to RT ether was added and the mixture was washed with water and 10% aqueous KHCO3 solution. The organic layer was then dried (MgSO4) and concentrated and the residue was purified by column chromatography (silica gel; ethyl acetate/cyclohexane 4:1) to yield 76 mg (48%) of 5-methyl-benzofuran-2-carbaldehyde as brown oil. 1HNMR (CDCl3, 300 MHz): δ 2.47 (s, 3H), 7.34 (d, J=8.7 Hz, 1H), 7.50 (m, 3H), 9.85 (s, 1H).
Reaction SMILES: [CH:1]1([C@H:4]([NH:8][C:9]([C:11]2[C:12]3[CH2:13][C@H:14]4[CH2:27][C@H:15]4[C:16]=3[N:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[N:18]=2)=[O:10])[C:5](O)=[O:6])[CH2:3][CH2:2]1.B.C([O-])(O)=O.[Na+]>C1COCC1>[CH:1]1([C@H:4]([NH:8][C:9]([C:11]2[C:12]3[CH2:13][C@H:14]4[CH2:27][C@H:15]4[C:16]=3[N:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[N:18]=2)=[O:10])[CH2:5][OH:6])[CH2:3][CH2:2]1
Reactant: O=C(N[C@H](C(=O)O)C1CC1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(N[C@H](CO)C1CC1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Temperature: 23 °C
Reaction time: 2.5 h
Yield: 42.7 %

Procedure:
To a solution of (S)-cyclopropyl-{[(1aR,5aR)-2-(2,4-difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-acetic acid (175 mg, 0.469 mmol) in THF (4 mL) was added a 1.0 M THF solution of borane (1.875 mL, 1.875 mmol). The reaction was stirred at 23° C. for 2.5 h. Saturated aqueous NaHCO3 (25 mL) was added. The mixture was extracted with dichloromethane (3×25 mL). The combined organic extracts were dried (MgSO4), filtered, then concentrated. The residue was purified by silica gel column chromatography followed by reversed-phase prep HPLC to give the title compound as a white solid (72 mg). LCMS m/z=360.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.35-0.42 (m, 2H), 0.48 (td, J=4.6, 3.4 Hz, 1H), 0.52-0.64 (m, 2H), 0.94-1.03 (m, 1H), 1.15 (td, J=7.8, 4.9 Hz, 1H), 2.09-2.14 (m, 1H), 2.24-2.31 (m, 1H), 2.94 (d, J=16.6 Hz, 1H), 3.05 (dd, J=16.6, 6.3 Hz, 1H), 3.18 (bs, 1H), 3.27-3.34 (m, 1H), 3.78-3.80 (m, 1H), 3.90 (dd, J=11.1, 3.0 Hz, 1H), 7.00-7.05 (m, 2H), 7.09 (d, J=6.4 Hz, 1H), 7.62-7.68 (m, 1H).
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1([CH3:24])[C:12](=[CH2:13])[S:11][C:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:9]([CH:22]=O)[CH2:8]1.C(N(CC)CC)C.CS([Cl:36])(=O)=O>O>[Cl:36]/[CH:22]=[C:9]1/[C:10](=[N:14]/[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)/[S:11][C:12](=[CH2:13])[C:7]([CH3:24])([CH3:6])[CH2:8]/1
Reactant: CS(=O)(=O)Cl
Reactant: C=C1SC(Nc2ccc(C)cc2)=C(C=O)CC1(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C=C1SC(=N\c2ccc(C)cc2)/C(=C/Cl)CC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an N,N-dimethylformamide (5 ml) solution of 5,5-dimethyl-6-methylene-2-p-tolylamino-5,6-dihydro-4H-thiopyran-3-carbaldehyde (0.26 g), triethylamine (0.14 g) and methanesulfonyl chloride (0.16 g) were added at 0° C. After raising the temperature to room temperature and further stirring for 1 hour, water was added thereto and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to obtain a crude product of {3-[1-chloro-(E)-methylidene]-5,5-dimethyl-6-methylene-tetra hydro-thiopyran-(2Z)-ylidene}-p-tolyl-amine.