Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C@H:11]1[CH2:17][N:16]([CH3:18])[C:15](=[O:19])[C@@H:14]([NH:20][C:21](=[O:37])[C@H:22]([O:35][CH3:36])[C@H:23]([OH:34])[C@@H:24]([OH:33])[C@H:25]([OH:32])/[CH:26]=[CH:27]/[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:13][CH2:12]1)=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C@H:11]1[CH2:17][N:16]([CH3:18])[C:15](=[O:19])[C@@H:14]([NH:20][C:21](=[O:37])[C@H:22]([O:35][CH3:36])[C@H:23]([OH:34])[C@@H:24]([OH:33])[C@H:25]([OH:32])/[CH:26]=[CH:27]/[C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:13][CH2:12]1
Reactant: CO[C@@H](C(=O)N[C@H]1CC[C@@H](OCCCCCCN=[N+]=[N-])CN(C)C1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H](C(=O)N[C@H]1CC[C@@H](OCCCCCCN)CN(C)C1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C(C)(C)C
Yield: 84.5 %

Procedure:
To a stirred solution of (E)-(2R,3R,4S,5R)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enoic acid [(3S,6R)-6-(6-azido-hexyloxy)-1-methyl-2-oxo-azepan-3-yl]-amide (0.13 g, 0.25 mmol) in THF (2 mL) is added H2O and triphenylphosphine (0.120 g, 0.5 mmol). After 8 h the reaction solution is evaporated under vacuum to give a semisolid residue that is dissolved in CH2Cl2 (10 mL), adsorbed on silica and chromatographed (CH2Cl2/NH3 to 25% CH3OH/CH2Cl2/NH3 gradient) to give 0.106 g (85%) of (E)-(2R,3R,4S,5R)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enoic acid [(3S,6R)-6-(6-amino-hexyloxy)-1-methyl-2-oxo-azepan-3-yl]-amide as a white solid. MS (ESI) 502.1 (M+H)+
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[CH2:5]=[CH:6][CH:7]([Cl:10])[CH2:8][Cl:9]>>[Cl:10][CH:7]([CH2:8][Cl:9])[CH2:6][CH2:5][Si:2]([Cl:4])([Cl:3])[Cl:1]
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CC(Cl)CCl
Product: ClCC(Cl)CC[Si](Cl)(Cl)Cl
Yield: 67.7 %

Procedure:
596 g trichlorosilane (4.4 moles, excess) and 500 g 3,4-dichlorobutene-1 (4 moles) are mixed. 0.4 g Pt(II)-acetyl acetonate are added to 30 ml of this mixture, at which time the temperature gradually rises by itself to 95° C. At this temperature, the remaining trichlorosilane/olefin mixture is added and allowed to react for an additional half hour at 92° C. Excess trichlorosilane and other readily volatile constituents are drawn off in a vacuum. The crude product obtained in this manner (826 g≅79.3% of theory) is subsequently purified by distillation. 705 g 3,4-dichlorobutyl trichlorosilane 67.7% of theory are obtained as the main fraction (see table 1 for composition data).
Reaction SMILES: C([SiH](CC)CC)C.[NH:8]([C:15]1[C:20]([CH:21](O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][N:18]=[C:17]([Cl:29])[N:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O>[NH:8]([C:15]1[C:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][N:18]=[C:17]([Cl:29])[N:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OC(c1ccccc1)c1cnc(Cl)nc1Nc1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Clc1ncc(Cc2ccccc2)c(Nc2ccccc2)n1
Reaction time: 64 h
Yield: 25.8 %

Procedure:
Triethylsilane (0.14 ml, 1.10 mmol) was added to a solution of 4-anilino-2-chloro-5-[1-hydroxy-1-phenylmethyl]pyrimidine (Method 58; 170 mg, 0.55 mmol) in trifluoroacetic acid (1.5 ml), and the mixture was stirred for 64 hours. Water (20 ml) was added and the mixture was neutralised with sodium carbonate powder and extracted with DCM (3×20 ml). The extracts were combined, washed with water (30 ml), dried, concentrated to a volume of 5 ml, and loaded on a Varian Mega Bond Elut column. Elution with DCM and concentration of the appropriate fractions gave the product as a yellow crystalline solid (42 mg, 26%). NMR (CDCl3): 3.93 (s, 2H), 6.45 (br s, 1H), 7.08 (m, 1H), 7.2-7.4 (m, 9H), 8.09 (s, 1H); MS (MH+): 296.2, 298.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][C:10]#[N:11])=[C:6]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])[N:5]=[C:4]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=2[F:31])[N:3]=1.[OH-].[K+]>CO.ClCCl>[F:31][C:25]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][S:22][C:4]1[N:5]=[C:6]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])[C:7]2[C:2](=[N:1][C:10]([NH2:11])=[CH:9][N:8]=2)[N:3]=1
Reactant: N#CCNc1c(N)nc(SCc2cccc(F)c2F)nc1SCc1cccc(F)c1F
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Nc1cnc2c(SCc3cccc(F)c3F)nc(SCc3cccc(F)c3F)nc2n1

Procedure:
A solution of the product from example 1 step b) (1.35 g) and potassium hydroxide (114 mg) in methanol (50 ml) and dichloromethane (20 ml) was stirred at room temperature for 24 hours. After evaporation in vacuo, the residue was purified by silica gel flash column chromatography, eluting with 5:1 dichloromethane:ethyl acetate, to give the subtitled compound as a pale yellow solid (0.37 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:27]=[CH:26][C:7]2[CH:8]3[CH2:14][CH2:13][C:12]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[C:17]([F:24])[C:16]=4[F:25])=[CH:11][CH:9]3[O:10][C:6]=2[C:5]=1[F:28])[CH3:2].C(OC1C=CC2C3CC=C(C4C=CC(OCC)=C(F)C=4F)CC3OC=2C=1F)C>C(OCC)(=O)C.C(O)C.[Ni]>[CH2:1]([O:3][C:4]1[CH:27]=[CH:26][C:7]2[CH:8]3[CH2:14][CH2:13][CH:12]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[C:17]([F:24])[C:16]=4[F:25])[CH2:11][CH:9]3[O:10][C:6]=2[C:5]=1[F:28])[CH3:2]
Reactant: CCOc1ccc(C2=CC3Oc4c(ccc(OCC)c4F)C3CC2)c(F)c1F
Agent: [Ni]
Agent: CCOc1ccc(C2=CCC3c4ccc(OCC)c(F)c4OC3C2)c(F)c1F
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOc1ccc(C2CCC3c4ccc(OCC)c(F)c4OC3C2)c(F)c1F
Reaction time: 18 h

Procedure:
7.4 g (about 19.0 mmol) of a mixture of (±)-(4aR*, 9bS*)-7-ethoxy-3-(4-ethoxy-2,3-difluorophenyl)-6-fluoro-1,2,4a,9b-tetrahydrodibenzofuran and (±)-(4aR*, 9bS*)-7-ethoxy-3-(4-ethoxy-2,3-difluorophenyl)-6-fluoro-1,4,4a,9b-tetrahydrodibenzofuran in 160 ml of ethyl acetate/ethanol mixture (3:1) are hydrogenated at 80° C. in the presence of 3.70 g of Raney nickel and 1.50 g of ion exchanger (weakly H-acidic) under hydrogen pressure (4.4 bar). After 18 h, the catalyst is filtered off, and the filtrate is concentrated to dryness. The crude product is recrystallised successively from isopropanol, n-heptane and ethanol, giving (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-3-(4-ethoxy-2,3-difluorophenyl)-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran as colourless solid (melting point 126° C.).
Reaction SMILES: [CH:1]([C:5]([CH3:10])([CH2:8][OH:9])[CH2:6][OH:7])([CH2:3][CH3:4])[CH3:2].[CH3:11][CH:12]1[CH:17]=[C:16]([CH3:18])[CH2:15][CH2:14][CH:13]1[CH:19]=O>>[CH:1]([C:5]1([CH3:10])[CH2:8][O:9][CH:19]([CH:13]2[CH2:14][CH2:15][C:16]([CH3:18])=[CH:17][CH:12]2[CH3:11])[O:7][CH2:6]1)([CH2:3][CH3:4])[CH3:2]
Reactant: CC1=CC(C)C(C=O)CC1
Reactant: CCC(C)C(C)(CO)CO
Product: CCC(C)C1(C)COC(C2CCC(C)=CC2C)OC1

Procedure:
An aqueous NaOH solution (30%, 420 g) was added at room temperature into a stirred mixture of 2,3-dimethyl pentanal (325 g, prepared as above in EXAMPLE II) and aqueous formaldehyde solution (CH2O) (30%, 722 g) while the reaction temperature was allowed to rise up to about 80° C. due to the exothermic reaction. After the addition was completed, the reaction mixture was cooled to about 40° C. The organic phases was separated and fractionally distilled to afford 2-sec-butyl-2-methyl-propane-1,3-diol (277 g). 2-sec-Butyl-2-methyl-propane-1,3-diol was reacted with 2,4-dimethyl-cyclohex-3-enecarbaldehyde to afford 5-sec-butyl-2-(2,4-dimethyl-cyclohex-3-enyl)-5-methyl-[1,3]dioxane according to previous disclosure (See, for example, U.S. Pat. No. 6,444,637).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12].[CH:16]1([C:19](=[S:21])[NH2:20])[CH2:18][CH2:17]1>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:19]([CH:16]2[CH2:18][CH2:17]2)[S:21][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:15]
Reactant: NC(=S)C1CC1
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1F
Product: COC(=O)c1nc(C2CC2)sc1-c1ccccc1F

Procedure:
prepared by reaction of 3-chloro-3-(2-fluoro-phenyl)-2-oxo-propionic acid methyl ester with cyclopropanecarbothioic acid amide. LC-MS: tR=1.00 min; [M+H]+=278.3.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([NH:28][C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:38])[CH2:10][CH2:9]1)[CH3:7].[OH-].[Na+]>CO>[C:29]([NH:28][C@H:17]1[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@H:15]([CH2:14][C@@H:13]([OH:38])[C@@H:12]3[C@@H:22]2[CH2:23][C@H:24]([OH:27])[C@@:25]2([CH3:26])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C@H:6]([CH3:7])[CH2:5][CH2:4][C:3]([OH:39])=[O:2])[CH2:16]1)(=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCC(=O)N[C@H]1CC[C@@]2(C)[C@@H](C1)C[C@@H](O)[C@@H]1[C@@H]2C[C@H](O)[C@]2(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCC(=O)N[C@H]1CC[C@@]2(C)[C@@H](C1)C[C@@H](O)[C@@H]1[C@@H]2C[C@H](O)[C@]2(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]12
Reaction time: 24 h
Yield: 82.1 %

Procedure:
0.5 g 3β-caprylamido-7α,12α-dihydroxy-5β-cholan-24-oic methylester (FIG. 5A-14) were dissolved in 20 ml methanol, treated with 2 ml 1N sodium hydroxide and left for 24 h at room temperature. The methanol was then distilled off, 10 ml water were added and the reaction mixture was extracted with ethyl acetate. The water fraction was then acidified with diluted hydrogen chloride, resulting in a white precipitate which was washed with water, to give 0.4 g of pure acid (FIG. 5A-15).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(O)CCC>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:2]2[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:12][CH2:11]1
Reactant: Fc1cccnc1Cl
Reactant: CN1CCNCC1
Solvent: CCCCO
Product: CN1CCN(c2ncccc2F)CC1

Procedure:
A solution of 2-chloro-3-fluoropyridine (1.0 g, 8.5 mmol) and N-methyl piperazine (4.26 g, 42.5 mmol) in n-butanol, 50 ml, is stirred at reflux for 18 hours. After concentrating under reduced pressure at 50° C., the residue is partitioned between ethyl ether and 50% NaOH solution. The ethyl ether extract is washed with a saturated sodium chloride solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The oily product is converted to the hydrogen fumarate salt, mp 148°-149° C., by treatment with fumaric acid in methanol and precipitation with ethyl ether.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17](Br)[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[CH:21]([Zn]C(C)C)([CH3:23])[CH3:22].C([Zn]CCC)CC.NCC1C(F)=C(OC2C=C(C=C(C(C)C)C=2)C#N)C(Cl)=CC=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH2:22][CH2:21][CH3:23])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(C)[Zn]C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)c1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CCC[Zn]CCC
Solvent: C1CCOC1
Product: CCCc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 70 °C
Yield: 55.2 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.400 g, 1.125 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.130 g, 0.112 mmol) were combined in THF (7 mL) and treated with an apparent mixture of diisopropylzinc and di-n-propylzinc (1 M in toluene, Aldrich 568112) (2.250 mL, 2.250 mmol) with stirring under an inert atmosphere. The reaction mixture was heated to 70° C. and stirred for 2 h. The reaction mixture was concentrated to dryness and partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted successively with EtOAc and 10% CH3OH/DCM to give a mixture of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(1-methylethyl)benzonitrile and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-propylbenzonitrile (1:6 ratio) (0.198 g, 0.621 mmol, 55.2% yield) as a clear oil. Diagnostic peaks in the aliphatic region of the NMR are as indicated below and were found to be in a ratio of ˜1:6, 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(1-methylethyl)benzonitrile to 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-propylbenzonitrile. 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(1-methylethyl)benzonitrile: 1H NMR (400 MHz, DMSO-d6) δ ppm 2.95 (spt, J=6.82 Hz, 1H), 1.19 (d, J=6.87 Hz, 6H). 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-propylbenzonitrile: 1H NMR (400 MHz, DMSO-d6) δ ppm 2.58 (t, J=7.55 Hz, 2H), 1.49-1.63 (m, 2H), 0.85 (t, J=7.33 Hz, 3H). LC-MS (ES−) m/z 317.12, 319.14 [M−1]. LC-MS (ES+) m/z 318.99, 320.99 [M+H].
Reaction SMILES: [C:1]([O:9][C:10]1([CH2:27][C:28]2[CH:33]=[CH:32][C:31](OC)=[CH:30][C:29]=2[OH:36])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:11]1=[O:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37](OC1C2C(=CC=C(C)C=2)N(CCCC(C)C)C1=O)(=[O:44])C1C=CC=CC=1>>[C:1]([O:9][C:10]1([CH2:27][C:28]2[CH:33]=[C:32]([O:44][CH3:37])[CH:31]=[CH:30][C:29]=2[OH:36])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:11]1=[O:26])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CC2(OC(=O)c3ccccc3)C(=O)N(CCCC(C)C)c3ccc(C)cc32)c(O)c1
Reactant: Cc1ccc2c(c1)C(OC(=O)c1ccccc1)C(=O)N2CCCC(C)C
Product: COc1ccc(O)c(CC2(OC(=O)c3ccccc3)C(=O)N(CCCC(C)C)c3ccc(C)cc32)c1

Procedure:
This compound was prepared in a similar manner to 3-(2-hydroxy-4-methoxybenzyl)-5-methyl-1-(4-methylpentyl)-2-oxoindolin-3-yl benzoate by reacting 5-methyl-1-(4-methylpentyl)-2-oxoindolin-3-yl benzoate with tert-butyl (2-(hydroxymethyl)-4-methoxyphenyl)carbonate. 1H-NMR δ 8.06 (d, 2H), 7.58 (t, 1H), 7.45 (t, 2H), 7.13 (d, 2H), 6.85 (d, 1H), 6.65 (m, 2H), 6.02 (bs, H), 5.88 (bs, OH), 3.70 (m, 2H), 3.47 (s, 3H), 3.38 (m, 2H), 2.32 (s, 3H), 1.48 (m, 1H), 1.27 (m, 2H), 1.12 (m, 2H), 0.84 (d, 6H). Calculated mass for C30H33NO5, 487.24, observed, 510.3 (M+Na).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH2:9][CH:8]=[C:7]([O:10][CH3:11])[CH2:6][CH:5]=1)[CH3:3].[CH2:12]([O:19][C:20](ON1C(=O)CCC1=O)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1COCC1>[CH2:12]([O:19][C:20]([NH:1][C@H:2]([C:4]1[CH2:9][CH:8]=[C:7]([O:10][CH3:11])[CH2:6][CH:5]=1)[CH3:3])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC1=CCC([C@H](C)N)=CC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC1=CCC([C@H](C)NC(=O)OCc2ccccc2)=CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of the above diene (31) in THF (250 mL) was added in one portion N-(benzyloxycarbonyloxy) -succinimide (40 g) (slightly exothermic) followed by after 15 min triethylamine (23 mL). The reaction was stirred for 16 h at room temperature, evaporated, taken up in ethyl acetate, washed with 1N Na2CO3, saturated NaCl, dried over MgSO4 and evaporated to give crude product (32). TLC Rf 0.26 (10% ethyl acetate, n-hexane); 1H NMR (CDCl3) δ1.24 (3H, d, J=7 Hz), 2.73(4H, br s), 3.55(3H, s), 4.27(1H, q), 4.64(1H, br s), 4.78(1H, br d), 5.12(2H, s), 5.64(1H, br s), 7.38 (5H, s).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH2:15][OH:16])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])C.O.[Li+].[OH-]>C1COCC1>[OH:16][CH2:15][C:12]1[CH:13]=[CH:14][C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[S:10][C:9]=2[CH:11]=1
Reactant: CCOC(=O)c1cc2ccc(CO)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccc(CO)cc2s1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
6-Hydroxymethyl-benzo[b]thiophene-2-carboxylic acid ethyl ester (2.4 g, 9.6 mmol, 1 eq) was dissolved in THF (10 mL, 4 vol) and water added (10 mL) along with LiOH (0.69 g, 28.8 mmol). The reaction mixture was stirred at 50° C. for 3 h and then concentrated to dryness and taken onto the next step without purification.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([C:12]2[CH:17]=[CH:16][C:15](F)=[C:14]([Cl:19])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].ClC(N(C)C)=C(C)C.[F:28][C:29]1[CH:30]=[C:31]([CH:39]([CH3:43])[C:40](O)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:40](=[O:41])[CH:39]([C:31]2[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([F:28])[CH:30]=2)[CH3:43])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:19])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(CN)n(-c2ccc(F)c(Cl)c2)n1
Reactant: CC(C(=O)O)c1ccc(S(C)(=O)=O)c(F)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)NCc1cc(C(C)(C)C)nn1-c1cccc(Cl)c1)c1ccc(S(C)(=O)=O)c(F)c1
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of (3-tert-butyl-1-(3-chloro-4-fluorophenyl)-1H-pyrazol-5-yl)methanamine (49 mg, 0.189 mmol) in DCM (1.3 mL) at room temperature and under nitrogen atmosphere was added 1-chloro-N,N,2-trimethyl-1-propenylamine (48 μL, 0.369 mmol), After 1 h of stirring were added 2-(3-fluoro-4-(methylsulfonyl)phenyl)propanoic acid (93 mg, 0.378 mmol) and N-ethyldiisopropylamine (0.11 mL, 0.662 mmol). The reaction mixture was stirred overnight at room temperature, washed with NaHCO3 solution (2×10 mL), dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (eluent: ethyl acetate/cyclohexane (2:1)) to give pure N-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-(3-fluoro-4-methylsulfonyl-phenyl)-propionamide (example compound D1) (66 mg, 71%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)C(O)=O.CN(C)C=O.C(Cl)(=O)[C:38]([Cl:40])=[O:39]>ClCCl>[O:1]=[C:2]1[C:10]2([C:11]3=[CH:21][C:20]4[CH2:19][CH2:18][O:17][C:16]=4[CH:15]=[C:12]3[O:13][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:25][C:24]=1[C:38]([Cl:40])=[O:39]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (2.13 g, 5.1 mmol) and N,N-dimethylformamide (0.001 mL, catalytic amount) in anhydrous dichloromethane (30 mL) was treated with oxalyl chloride (4.50 mL, 5.1 mmol). The reaction mixture was stirred at ambient temperature for 3 h. The crude product was concentrated in vacuo to afford 3-(((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-1′-yl)methyl)benzoyl chloride as a light yellow solid. A solution of 3-((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-1′-yl)methyl)benzoyl chloride (0.27 g, 0.6 mmol), cyclohexanemethylamine (0.17 mL, 1.3 mmol), triethylamine (0.44 mL, 3.2 mmol), and 4-(dimethylamino)pyridine (0.005 g, catalytic amount) in anhydrous dichloromethane (5 mL), was stirred at ambient temperature for 20 h under nitrogen. The reaction mixture was diluted with dichloromethane (10 mL) and aqueous citric acid (10 mL) and the phases were separated. The organic phase was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography with ethyl acetate in hexanes (0% to 100% gradient) to afford N-(cyclohexylmethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide (0.33 g, 65%) as a colourless solid: 1H NMR (300 MHz, CDCl3) δ7.80 (s, 1H), 7.63 (d, J=7.4 Hz, 1H), 7.48-7.37 (m, 2H), 7.23-7.15 (m, 2H), 7.08-7.00 (m, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.43 (s, 1H), 6.19-6.09 (m, 1H), 5.08 (d, J=15.7 Hz, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.91 (d, J=15.7 Hz, 1H), 4.72 (d, J=9.0 Hz, 1H), 4.55 (t, J=8.6 Hz, 2H), 3.33-3.23 (m, 2H), 3.07-2.95 (m, 2H), 1.82-1.64 (m, 5H), 1.34-1.13 (m, 4H), 1.07-0.86 (m, 2H); MS (ES+) m/z 509.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[C:10]1[C:11]([OH:16])=[CH:12][CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(Br)C=C.[CH2:27]([O:30]CC=C)[CH:28]=[CH2:29].C(C1C=CC=C(C2C(Cl)=CC(Cl)=CC=2Cl)C=1O)C=C.ClC1C=C(C=CC=1)C(OO)=O>C1(C)C=C(C)C=C(C)C=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[C:10]1[C:11]2[O:16][CH:28]([CH2:27][OH:30])[CH2:29][C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: Oc1ccccc1-c1c(Cl)cc(Cl)cc1Cl
Reactant: C=CCOCC=C
Agent: C=CCc1cccc(-c2c(Cl)cc(Cl)cc2Cl)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Solvent: Cc1cc(C)cc(C)c1
Solvent: C=CCBr
Product: OCC1Cc2cccc(-c3c(Cl)cc(Cl)cc3Cl)c2O1
Yield: 95 %

Procedure:
Treatment of 2,4,6-trichlorobromobenzene (14.5 g, 55.69 mmol) with 2-methoxybenzeneboronic acid (12.69 g, 83.54 mol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.656 g, 0.835 mmol), and potassium carbonate (19.21 g, 139.22 mmol) generally according to the procedure described for Intermediate 37 provided 9.8 g (61%) of 2′ 4′,6′-trichloro-1,1′-biphenyl-2-yl methyl ether. To a solution of 2′4′,6′-trichloro-1,1′-biphenyl-2-yl methyl ether (9.8 g, 34.08 mmol) in dichloromethane (100 mL) cooled to −78° C. was added boron tribromide (9.38 g, 1.0 M in dichloromethane) generally according to the procedure described for Intermediate 163 provided provided 9.2 g of a yellow solid. Treatment of 2′,4′,6′-trichloro-1,1′-biphenyl-2-ol (9.17 g, 33.52 mmol) with potassium carbonate (18.53 g, 134.1 mmol) and allyl bromide (4.46 g, 36.87 mol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-2′,4′,6′-trichloro-1,1′-biphenyl-2-ol. Treatment of 3-allyl-2′,4′,6′-trichloro-1,1′-biphenyl-2-ol. (10.35 g, 33.00 mmol) with 3-chloroperoxybenzoic acid (17.08 g, 99.00 mmol, 77%) followed by potassium carbonate (11.40 g, 82.51 mmol) generally according to the procedure described for Intermediate 9 afforded 10.4 g (95%) of (±)-[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment of (±)-[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (10.38 g, 31.49 mmol) with p-toluenesulfonyl chloride (7.20 g, 37.79 mol) generally according to the procedure described for Intermediate 10 gave 10.5 g (68%) of (±)-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. mp 178-180° C.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([CH2:13][CH2:14][OH:15])[CH:10]([CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[OH-].[OH-].[Pd+2].CO>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH:10]3[CH:11]([CH2:13][CH2:14][OH:15])[CH2:12][NH:8][CH2:9]3)[CH2:18][CH2:19]2)=[CH:28][CH:27]=1
Reactant: OCCC1CN(Cc2ccccc2)CC1CN1CCC(c2ccc(F)cc2)CC1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: OCCC1CNCC1CN1CCC(c2ccc(F)cc2)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
A mixture of 0.89 g (2.3 mmol) of 1-benzyl-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-hydroxyethylpyrrolidine, 2.9 g (17.7 mmol) of ammonium formate and 0.39 g of Pearlman's catalyst [Pd(OH)2/C] in 30 mL of MeOH was stirred at 70° C. for 1 h. The reaction mixture was filtered through a thin pad of Celite and the filtrate was concentrated to give 0.7 g of the title compound.