Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27].C(N(CC)CC)C>O1CCOCC1>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:16]2[CH:21]=[CH:20][C:19]([S:22](=[O:23])(=[O:24])[NH2:25])=[CH:18][C:17]=2[N+:26]([O-:28])=[O:27])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Temperature: 90 °C

Procedure:
Tert-butyl 4-aminopiperidine-1-carboxylate (8.63 g) was dissolved in 1,4-dioxane (250 mL), and 4-chloro-3-nitrobenzenesulfonamide (6.00 g) was added followed by triethylamine (10.60 mL). The solution was heated at 90° C. for 20 hours and then cooled. The solvent was removed under vacuum, and the material was purified by flash column chromatography on silica gel using 50% ethyl acetate in hexanes, increasing to 100% ethyl acetate and increasing further to 20% methanol in dichloromethane.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=2[O:19]CC2C=CC=CC=2)[O:3]1>CCOC(C)=O.[Pd]>[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:27])[O:3][B:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:12]=[CH:11][C:10]=2[OH:19])[O:5]1
Reactant: CC1(C)OB(c2cc(C(F)(F)F)ccc2OCc2ccccc2)OC1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cc(C(F)(F)F)ccc2O)OC1(C)C
Reaction time: 1 h

Procedure:
10% Pd/C (0.5 g) was added to a solution of the product from step (i) in EtOAc (80 ml) and hydrogenated at RT and 1 bar for 1 h, and for a further 3 h at 3 bar. The catalyst was removed by filtration and the filtrate evaporated to leave a solid product. Yield 4.2 g.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:13]([F:16])([F:15])[F:14])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)=[N:5]1)[CH:2]=[CH2:3].B(Br)(Br)Br.C1CCCCC=1>>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:13]([F:16])([F:15])[F:14])[C:6]([C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1nc(-c2ccc(OC)cc2)c2cccc(C(F)(F)F)c21
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: C=CCn1nc(-c2ccc(O)cc2)c2cccc(C(F)(F)F)c21
Yield: 94.3 %

Procedure:
Prepared according to Method D step C from 1-allyl-3-(4-methoxyphenyl)-7-trifluoromethyl-1H-indazole (0.027 g, 0.08 mmol), boron tribromide (0.10 mL, 1.05 mmol) and 0.3 mL of cyclohexene to give the product (0.024 g) as a grey solid.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:6][CH:5]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:1][CH:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:19][CH:18]=1)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(COc1ccc(Cl)cc1)c1ccccc1
Reactant: BrBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)C(Br)Oc1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
Bromine (11.6g) in chloroform (40ml) was added dropwise to a stirred solution of 4-chloro-α-phenoxyacetophenone (18.8g) in chloroform (1200ml) containing dibenzoyl peroxide (50 mg) under photoflood illumination. The reaction was complete after 2 hours, and the chloroform was removed under reduced pressure to give α-bromo-4-chloro-α-phenoxyacetophenone which was used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]4[C:23]5[CH:35]=[CH:34][CH:33]=[N:32][C:24]=5[NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:21]4=[N:20][C:19]=3[C:36]3[CH:41]=[CH:40][C:39]([N:42]4[CH2:47][CH2:46][CH2:45][CH2:44][C:43]4=[O:48])=[CH:38][CH:37]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.[ClH:50].O1CCOCC1>C(Cl)Cl>[ClH:50].[ClH:50].[ClH:50].[NH2:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]4[C:23]5[CH:35]=[CH:34][CH:33]=[N:32][C:24]=5[NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:21]4=[N:20][C:19]=3[C:36]3[CH:37]=[CH:38][C:39]([N:42]4[CH2:47][CH2:46][CH2:45][CH2:44][C:43]4=[O:48])=[CH:40][CH:41]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(N5CCCCC5=O)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3c(-c4ccc(N5CCCCC5=O)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 84.1 %

Procedure:
tert-Butyl[1-(4-{2-[4-(2-oxopiperidin-1-yl)phenyl]-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl}phenyl)cyclobutyl]carbamate (31.9 mg, 0.0489 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 19 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (27.2 mg, 84.1%) as yellow solid. 1HNMR (DMSO-d6) 500 MHz δ: 8.80-8.69 (m, 3H), 8.65 (br s, 1H), 8.13-8.09 (m, 1H), 7.98-7.93 (m, 1H), 7.59-7.54 (m, 2H), 7.51-7.47 (m, 2H), 7.41-7.29 (m, 4H), 7.25-7.21 (m, 2H), 7.16-7.11 (m, 1H), 6.93-6.88 (m, 1H), 6.75 (dd, J=7.7, 4.9 Hz, 1H), 3.62-3.57 (m, 2H), 2.62-2.47 (m, 4H), 2.41-2.35 (m, 2H), 2.24-2.13 (m, 1H), 1.90-1.78 (m, 5H); LCMS: 553 [M+H].
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([F:24])=[C:21]([CH:23]=1)[NH2:22]>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([F:24])=[C:21]([NH:22][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[CH:4][C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:23]=1
Reactant: Nc1cc(Cl)ccc1F
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Product: CCOC(=O)c1cnc2ccnn2c1Nc1cc(Cl)ccc1F
Yield: 71.2 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (2.0 g, 9.65 mmol) and 5-chloro-2-fluoroaniline (1.26 g, 8.69 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (2.07 g, 64%) was obtained.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:11]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18])[CH:12]([CH3:14])[CH3:13]>>[CH2:11]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:7](=[O:9])[CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH:12]([CH3:14])[CH3:13]
Reactant: O=C(O)CC1CCCC1
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)CC1CCCC1

Procedure:
Following General Procedure B above, and using cyclopentylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B above), the title compound was prepared as a solid having a melting point of 62° C.-64° C. The reaction was monitored by tlc on silica gel (Rf=0.37 in 1:3 EtOAc:hexane) and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[CH3:12][N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][CH2:19][NH2:20].[Na]>ClCCl>[S:1]1[C:5]([CH2:6][NH:20][CH2:19][CH2:18][CH:14]2[CH2:15][CH2:16][CH2:17][N:13]2[CH3:12])=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=Cc1cc2ccccc2s1
Reactant: CN1CCCC1CCN
Agent: [Na]
Solvent: ClCCl
Product: CN1CCCC1CCNCc1cc2ccccc2s1
Yield: 26.6 %

Procedure:
Experimental condition analogous to Example 5, from benzo[b]thiophen-2-carbaldehyde 0.18 g (1.1 mmol), 2-(1-methyl-pyrrolidin-2-yl)-ethylamine 0.14 g (1 mmol), and sodium triacethoxyborohydride 0.31 g (1.5 mmol), in 10 mL dichloromethane. Purification using silica gel chromatography, elution with dichloromethane-methanol-ammonium hydroxide, 9-1-0.25, gave 73 mg of compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][C@@H:11]1[C@@:41]2([CH3:42])[C:15](=[CH:16][CH2:17][C@@H:18]3[C@@H:40]2[CH2:39][CH2:38][C@@:37]2([CH3:43])[C@H:19]3[CH2:20][CH2:21][C@@H:22]2[C@H:23]([CH3:36])[CH2:24][O:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:14][C@@H:13]([O:44]C(=O)C)[CH2:12]1)(=O)C.O1CCCC1.C(OCC)(=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1>[OH:10][C@@H:11]1[C@@:41]2([CH3:42])[C:15](=[CH:16][CH2:17][C@@H:18]3[C@@H:40]2[CH2:39][CH2:38][C@@:37]2([CH3:43])[C@H:19]3[CH2:20][CH2:21][C@@H:22]2[C@H:23]([CH3:36])[CH2:24][O:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:14][C@@H:13]([OH:44])[CH2:12]1
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)COS(=O)(=O)c5ccc(C)cc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](C)[C@H]2CC[C@H]3[C@@H]4CC=C5C[C@@H](O)C[C@H](O)[C@]5(C)[C@H]4CC[C@]23C)cc1
Reaction time: 0.5 h

Procedure:
In a 2.5 l 4-neck flask equipped with a stirrer, 500 ml dropping funnel with pressure equilizer, thermometer and argon inlet, 800 ml of tetrahydrofuran (product from freshly-opened bottle was stored for 16 hr. over molecular sieves) at room temperature was added in one portion with stirring to 10.84 g (0.28 mol) of lithium aluminum hydride. The suspension was cooled to -20°, and, during cooling and stirring for 30 min., a solution of 26.5 g crude (20S)-1α,3β-diacetyloxy-20-methyl-21-p-toluenesulfonyloxypregn-5-ene in 450 ml tetrahydrofuran under an argon atmosphere was dripped into the flask in such a way that the temperature did not surpass -18°. After stirring for 1.5 hr. under argon at -20°, 1.2 l of tetrahydrofuran--ethyl acetate (1:1) was added to the suspension over a period of 30 min. in such a way that the temperature did not surpass -18°. The cold reaction mixture was poured into a stirred solution, precooled to 0°, of 0.8 l of 2 M potassium sodium tartrate solution. The organic solvent was removed under vacuum at 40°, and the aqueous residue was extracted first with 500 ml and then twice with 300 ml (total of 1.1 l) of ether. The ether extracts were washed successively 2 times with 250 ml of water and 2 times with 250 ml of sat. NaCl solution, combined and dried over sodium sulfate. After removal of the solvent under reduced pressure at 40°, the residue amounted to 24.1 g of crude (20S)-1α,3β-dihydroxy-20-methyl-21-p-toluenesulfonyloxypregn-5-ene (the crude product still contained some unreacted triol because of incomplete tosylation).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10])[OH:22]
Reactant: COc1ccc(Cl)cc1Br
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: COc1ccc(Cl)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 93.1 %

Procedure:
With 14.6 g of 2-bromo-4-chloro anisole and 8.00 g of 5-chloroisatin as starting materials, 13.3 g of the title compound (yellow solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([F:10])([F:9])[F:8])=[C:4]([CH2:11][OH:12])[CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:23][CH:22]([O:24][C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=2O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[CH2:23][CH:22]([O:24][C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=2[O:12][CH2:11][C:4]2[CH:3]=[C:2]([CH3:1])[O:6][C:5]=2[C:7]([F:10])([F:8])[F:9])[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1cc(CO)c(C(F)(F)F)o1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Product: Cc1cc(COc2ccc(Cl)cc2OC2CN(C(=O)OC(C)(C)C)C2)c(C(F)(F)F)o1

Procedure:
Synthesized from the title compound of Step A and 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester using general procedure 7. MS (ESI): mass calcd. for C21H23ClF3NO5, 461.1; m/z found, 485.9 [M+Na]+. 1H NMR 6.91 (dd, J=8.6, 2.3 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H), 6.55 (d, J=2.3 Hz, 1H), 6.22 (s, 1H), 5.07-5.00 (m, 2H), 4.90-4.81 (m, 1H), 4.30 (ddd, J=9.7, 6.5, 0.8 Hz, 2H), 4.06 (dd, J=9.8, 4.0 Hz, 2H), 2.34 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]=[C:8]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[C:9]([OH:11])=[O:10].[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[C@@H:19](O)[CH2:18]2>CN(C)C=O.C(Cl)(Cl)Cl>[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[C@@H:19]([O:10][C:9](=[O:11])[C:8](=[O:7])[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[CH2:18]2
Reactant: O=C(O)C(=O)c1ccco1
Reactant: O[C@H]1CN2CCC1CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(O[C@H]1CN2CCC1CC2)C(=O)c1ccco1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.8 %

Procedure:
Oxalyl chloride (9.75 ml, 0.112 mol) was added to a solution of oxofuran-2-ylacetic acid (10 g, 0.071 mol) and dimethylformamide (one drop) in 150 ml of chloroform (etanol free) at 0° C. The mixture was stirred and allowed to warm at room temperature. After five hours the solvent was evaporated. The residue was dissolved in chloroform and evaporated again. This procedure was repeated two times. The product obtained was dissolved in CHCl3 (150 ml) and a solution of 3(R)-quinuclidinol (10.90 g, 0.086 mol) in CHCl3 (150 ml) was added to this at 0° C. The mixture was stirred and allowed to warm at room temperature. After 15 h at r.t., the mixture was washed with 10% aqueous potassium carbonate, then with water, dried over Na2SO4 and evaporated to give 9.34 g (52.5%) of the title compound as a dark oil. Estructure confirmed by NMR.
Reaction SMILES: [C:1](/[N:3]=[C:4](\[N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)/[N:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=3[CH3:27])[CH2:15][CH2:14]2)=[O:12])[C@@H:7]([C:28](OC)=[O:29])[CH2:6]1)#[N:2].[NH2:38][OH:39]>CO>[C:1](/[N:3]=[C:4](\[N:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)/[N:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=3[CH3:27])[CH2:17][CH2:18]2)=[O:12])[C@@H:7]([C:28]([NH:38][OH:39])=[O:29])[CH2:6]1)#[N:2]
Reactant: NO
Reactant: COC(=O)[C@H]1CN(/C(=N/C#N)N2CCCCC2)CC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1
Solvent: CO
Product: Cc1cc(C#N)ccc1N1CCN(C(=O)[C@H]2CCN(/C(=N/C#N)N3CCCCC3)C[C@@H]2C(=O)NO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl (3R,4S)-1-[(E)-(cyanoimino)(piperidin-1-yl)methyl]-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-3-carboxylate (53.30 mg, 0.0001054 mol) in anhydrous methanol (1.110 mL, 0.02740 mol) at rt was added the above 1.50 M of hydroxylamine in methanol (1.40 mL). The reaction mixture was stirred at rt for 2 h. LCMS showed the reaction was done. The reaction was quenched with saturated aqueous NH4Cl, extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC with 5-95% MeCN/H2O to give the product. MS (ESI): (M+H)+=507.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12](Cl)=[O:13])[CH2:8]2.[CH3:15][O:16][C:17](=[O:31])[C@@:18]([CH3:30])([CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)[NH2:19].C(N(CC)CC)C>C1COCC1>[CH3:15][O:16][C:17](=[O:31])[C@@:18]([CH3:30])([CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)[NH:19][C:12]([O:11][CH:2]1[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)=[O:13]
Reactant: COC(=O)[C@](C)(N)Cc1c[nH]c2ccccc12
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@](C)(Cc1c[nH]c2ccccc12)NC(=O)OC1C2CC3CC(C2)CC1C3
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
To a stirred solution of 2-adamantylchloroformate (0.965 g, 4.5 mmol) in dry THF (10 mL) was added a solution of α-methyl-D-tryptophan methyl ester (0.928 g, 4 mmol) in dry THF (20 mL) followed by a solution of triethylamine (0.808 g, 8 mmol) in dry THF (20 mL) dropwise. After 15 minutes, the reaction mixture was filtered, the solvent removed in vacuo and column chromatographed using 2% MeOH:98% CH2Cl2 as eluant to yield the title compound (1.42 g, 89%) as a syrup. IR (film) 1740-1695 b.r cm-1 ; NMR (CDCl3) δ1.50-1.60 (2H, m), 1.67 (3H, s), 1.70-2.10 (12H, m), 3.38 (1H, d, J=14.5 Hz), 3.50-3.60 (1H, br.s), 3.68 (3H, s), 4.86 (1H, br.s), 5.28 (1H, br.s), 6.93 (1H, d, J 2.4 Hz); 7.04-7.10 (2H, m), 7.33 (1H, d, J 8.2 Hz) 7.54 (1H, d, J 7.8 Hz), 8.18 (1H, br.s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([NH:19][CH3:20])(=[O:18])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:30](S(Cl)(=O)=O)[CH2:31][CH2:32]CC.C(N)C(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([NH:19][CH2:20][CH:31]([CH3:32])[CH3:30])(=[O:17])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCCCCS(=O)(=O)Cl
Reactant: CNS(=O)(=O)CCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Solvent: CC(C)CN
Product: CC(C)CNS(=O)(=O)CCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Yield: 66 %

Procedure:
4-chloro-N-[2,5-dichlorophenyl]-N-[4-[(2-methylpropyl amino)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide was prepared analogous to 4-chloro-N-[2,5-dichlorophenyl]-N-[4 [(methylamino)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide by reacting (4R)-4-[2,5-dichlorophenyl][4-chlorophenyl)sulfonyl]-amino]pentylsulfonyl chloride with iso-butylamine. Yield=66%; MS (ESI+), 541 (M+H)+.
Reaction SMILES: [Cl:1][Si:2]([CH3:10])([CH3:9])[CH:3]=[CH:4][Si:5]([Cl:8])([CH3:7])[CH3:6].ClC([SiH2][CH:15]=[C:16]([SiH2]C(Cl)Cl)CC)Cl>>[Cl:1][Si:2]([CH3:10])([CH3:9])[CH2:3][CH:4]([Si:5]([Cl:8])([CH3:7])[CH3:6])[CH2:15][CH3:16]
Reactant: C[Si](C)(Cl)C=C[Si](C)(C)Cl
Reactant: CCC(=C[SiH2]C(Cl)Cl)[SiH2]C(Cl)Cl
Product: CCC(C[Si](C)(C)Cl)[Si](C)(C)Cl

Procedure:
Example 1 was repeated with the modification that, instead of 300.0 g (1.41 mol) of 1,2-bis(chlorodimethylsilyl)ethene, 300.0 g (1.24 mol) of 1,2-bis(dichloromethylsilyl)but-1-ene were used. The results are summarized in Table 1.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([NH2:31])[C:28]([F:32])=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:6]=1I.[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O>[NH2:31][C:29]1[C:28]([F:32])=[CH:27][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:6]=2[C:37]2[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=2)=[C:2]([F:1])[CH:30]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc(Oc2cc(F)c(N)cc2F)c1I
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1cc(-c2c(Oc3cc(F)c(N)cc3F)ccnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a degassed solution of 4-(2,5-difluoro-4-aminophenoxy)-3-iodo-2-[bis[(1,1-dimethylethoxy)carbonyl]amino]pyridine (0.7 g, 1.24 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.52 g, 2.48 mmol) in dioxane (15 mL) was added K2CO3 (0.51 g, 3.7 mmol) in water (3 mL). Tetrakis (triphenylphosphine)Palladium(0) (0.14 g, 0.12 mmol) was added and the reaction mixture was stirred at 100° C. for 3 h. The mixture was diluted with water (40 mL) and EtOAc (50 mL). The layers were separated, and the aq. layer was extracted with EtOAc (20 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc-hexanes) to afford 4-(4-amino-2,5-difluorophenoxy)-3-(1-methyl-1H-pyrazol-4-yl)-2-[bis[(1,1-dimethylethoxy)carbonyl]amino]pyridine as a colorless foam (0.52 g, 81% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.17 (d, J=5.6 Hz, 1H), 7.84 (s, 1H), 7.48 (d, J=0.8 Hz, 1H), 7.21 (dd, J=11.2 Hz, 7.6 Hz, 1H), 6.70 (m, 2H), 5.50 (s, 2H), 3.86 (s, 3H), 1.25 (s, 18H); MS (ESI) m/z: 518.3 (M+H+).
Reaction SMILES: [NH2:1][C:2](=[N:44][OH:45])[C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=1)[CH2:6][O:7][NH:8][C:9]([CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:12]1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[Cl:40])=[O:10].C(#N)C.[C:49](N1C=CN=C1)(N1C=CN=C1)=[S:50].C1CCN2C(=NCCC2)CC1>C(OCC)(=O)C>[Cl:40][C:34]1[CH:35]=[C:36]([Cl:39])[CH:37]=[CH:38][C:33]=1[CH:12]1[CH:11]([C:9]([NH:8][O:7][CH2:6][C:5]2[CH:41]=[CH:42][CH:43]=[C:3]([C:2]3[NH:1][C:49](=[S:50])[O:45][N:44]=3)[CH:4]=2)=[O:10])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[NH:28][S:29]([CH3:32])(=[O:31])=[O:30]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2cccc(C(N)=NO)c2)C1c1ccc(Cl)cc1Cl
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2cccc(-c3noc(=S)[nH]3)c2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
To a mixed liquid of 300 mg of (3RS,4RS)—N-({3-[amino(hydroxyimino)methyl]benzyl}oxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 30 ml of acetonitrile were added 132 mg of 1,1′-carbonothioyl bis(1H-imidazole) and 0.27 ml of DBU under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated and then added with 50 ml of water, and 1 M hydrochloric acid was added thereto until the pH reached 4 to 5. After extracting with ethyl acetate, washing with a saturated aqueous sodium chloride solution and drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent:chloroform-methanol). The crude purified product thus obtained was added with ethyl acetate and collected by filtration to obtain 61 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-{[3-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl]oxy}-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white solid.
Reaction SMILES: S([O-])(=O)(=O)C.[CH2:6]([N:13]1[CH2:17][CH2:16][CH:15](O)[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C-:19]#[N:20].[Na+]>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O>[CH2:6]([N:13]1[CH2:17][CH2:16][CH:15]([C:19]#[N:20])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [C-]#N
Reactant: OC1CCN(Cc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CC1CCN(Cc2ccccc2)C1
Temperature: 82.5 °C
Reaction time: 16 h
Yield: 75.7 %

Procedure:
This transformation was carried out using the method described in C. Thomas et. al. reference 97. The mesylate of racemic 1-benzyl-pyrrolidin-3-ol (0.039 mol, 10 g), prepared as described above, sodium cyanide (0.24 mol, 15 g) and tetrabutylammonium cyanide (10 g, 0.037 mol) in 75 mL of DMSO was stirred at 80-85° C. for 16 h. The reaction mixture was partitioned between diethyl ether and sat. aq sodium bicarbonate. The aqueous layer was extracted twice with ether and the combined organic layer was washed successively with sodium bicarbonate, water, and sat aq. NaCl. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by flash chromatography over silica gel using a gradient of 20 to 30% ethyl acetate in hexane to afford 5.5 g of the desired product.