Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:31]([O:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:32]>>[CH3:36][C:35]([CH3:38])([CH3:37])[CH2:34][O:33][C:31](=[O:32])[N:14]([C@@H:13]1[C@@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][N:11]([C:16]([CH:18]2[CH2:19][CH2:20][N:21]([C:24]([C:26]3([CH3:29])[CH2:28][CH2:27]3)=[O:25])[CH2:22][CH2:23]2)=[O:17])[CH2:12]1)[CH3:15]
Reactant: CN[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)COC(=O)Cl
Product: CN(C(=O)OCC(C)(C)C)[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 2 (step b), the title compound rac-{(3R,4S)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 2,2-dimethyl-propyl ester was prepared from rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using neopentyl chloroformate instead of 4-fluorophenyl chloroformate and was obtained as a yellow foam. MS m/e: 552.3 [M]+.
Reaction SMILES: C1(O[C:8]([N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)=[O:9])C=CC=CC=1.[CH2:23]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH2:35])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN1C(=O)CCC1>[C:19]([O:18][C:16](=[O:17])[NH:15][C@@H:12]1[CH2:13][CH2:14][N:10]([C:8](=[O:9])[NH:35][C@@H:32]2[CH2:33][CH2:34][N:30]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31]2)[CH2:11]1)([CH3:20])([CH3:21])[CH3:22]
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)Oc2ccccc2)C1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)N[C@@H]2CCN(Cc3ccccc3)C2)C1
Temperature: 100 °C

Procedure:
(R)-3-tert-Butoxycarbonylamino-pyrrolidine-1-carboxylic acid phenyl ester (1 eq.) and (R)-1-benzyl-pyrrolidin-3-ylamine (1 eq.) are dissolved in NMP and heated at 100° C. for 1 hour.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH:8]1[CH2:11][CH2:10][CH2:9]1.[F:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([NH:18][NH2:19])=O.Cl.C(N(CC)CC)C>CC1C=CC(C)=CC=1>[Cl:1][C:2]1[C:7]([CH:8]2[CH2:11][CH2:10][CH2:9]2)=[CH:6][C:5]2[N:4]([C:16]([C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=3[F:13])=[N:18][N:19]=2)[N:3]=1
Reactant: Clc1cc(C2CCC2)c(Cl)nn1
Reactant: NNC(=O)c1ccccc1F
Agent: Cl
Solvent: Cc1ccc(C)cc1
Solvent: CCN(CC)CC
Product: Fc1ccccc1-c1nnc2cc(C3CCC3)c(Cl)nn12
Yield: 49 %

Procedure:
A mixture of 3,6-dichloro-4-cyclobutylpyridazine from above (3.0 g, 14.7 mmol), 2-fluorobenzhydrazide (3.0 g, 19.5 mmol) and triethylamine hydrochloride (3.0 g, 21.8 mmol) in p-xylene (50 ml) was stirred and heated at reflux under a stream of nitrogen for 20 hours. Upon cooling the volatiles were removed in vacuo. The residue was partitioned between dichloromethane and water. The aqueous was basified by the addition of solid potassium carbonate. Some dark insoluble material was removed by filtration at this stage. The aqueous was further extracted with dichloromethane (×2). The combined extracts were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel eluting with 20%→30% ethyl acetate/dichloromethane to give the title compound (2.2 g, 49%) as a light-brown solid. Data for the title compound: 1H NMR (250 MHz, CDCl3) δ 1.85-2.08 (1H, m), 2.08-2.30 (3H, m), 2.38-2.64 (2H, m), 3.62-3.84 (1H, m), 7.19-7.46 (2H, m), 7.46-7.67 (1H, m), 7.80-7.96 (1H, m), 7.99 (1H, s), MS (ES+) m/e 303 [MH]+, 305 [MH]+.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:35]=[N:36][NH:37][CH:38]=3)=[C:30]([O:39]C)[N:29]=2)=[CH:10]\[C@@H:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[C:14](=[O:27])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.O>O1CCOCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6](/[C:9](/[C:28]2[NH:29][C:30](=[O:39])[C:31]([C:34]3[CH:38]=[N:37][NH:36][CH:35]=3)=[CH:32][CH:33]=2)=[CH:10]\[C@H:11]2[CH2:12][CH2:13][C:14](=[O:27])[N:15]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])=[CH:7][CH:8]=1
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(Cl)cc2)c2ccc(-c3cn[nH]c3)c(OC)n2)c(OC)c1
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(Cl)cc2)c2ccc(-c3cn[nH]c3)c(=O)[nH]2)c(OC)c1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
48% hydrobromic acid (1.25 mL) was added to a solution of (5R)-5-{(E)-2-(4-chlorophenyl)-2-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (63 mg) in 1,4-dioxane (1.25 mL), and the mixture was stirred at 65° C. for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=10:0→9:1) to give 6-{(E)-1-(4-chlorophenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-3-(1H-pyrazol-4-yl)pyridin-2(1H)-one as a yellow amorphous (100 mg, 81%).
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21](=O)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38]N)=[CH:34][CH:33]=1>>[CH3:1][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[C:36]4[C:35](=[CH:34][CH:33]=[C:32]([CH3:31])[CH:37]=4)[NH:38][C:21]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccccc3)CC2)c1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3ccccc3)c(CCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(4-oxo-4-phenylbutyl)-4-piperidinyl]phenyl}propanamide and 1-(4-methylphenyl)hydrazine hydrochloride: ESMS m/e: 480.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16](Cl)(=[O:20])[CH2:17][CH2:18][CH3:19]>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:16](=[O:20])[CH2:17][CH2:18][CH3:19])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: CCCC(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Product: CCCC(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1

Procedure:
The title compound was prepared according to the general procedure for acylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using butyryl chloride (59 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]butanamide (0.045 g).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH2:14]([NH2:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>>[CH3:16][C:15]([CH3:18])([CH3:17])[CH2:14][NH:19][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: CC(C)(C)CN
Product: CC(C)(C)CNc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 1A from 4-fluoro-2-(trifluoromethyl)benzonitrile and neopentylamine: MS (El) m/z 256 (M+, 9%), 239 ({[M−H]—CH3}+, 32%), 199 ([M-tbutyl]+, 78%), 179 ([M-neopentylamine]+, 100).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=2)[NH:18][CH:17]=1)[C:8]([O:10][CH3:11])=[O:9].[CH3:28]I>O1CCCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=2)[N:18]([CH3:28])[CH:17]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc([N+](=O)[O-])cc23)c(OC)c1
Reaction time: 0.17 h
Yield: 96 %

Procedure:
Sodium hydride (212 milligrams) was added to a solution of methyl 3-methoxy-4-(5-nitroindol-3-ylmethyl)benzoate (1.8 grams) in 60 mL of dry tetrahydrofuran. After stirring for 10 minutes, methyl iodide (753 milligrams) was added and the reaction was stirred at room temperature for 2 hours. The volatiles were evaporated and the residue dissolved in ethyl acetate. The ethyl acetate layer was washed with water, dried over sodium sulfate and evaporated. The residue was purified on silica gel with dichloromethane to give 1.8 grams product, m.p. 151°-153°.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:47][CH:48]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:49]1[CH:54]=[CH:53][C:52]([P:55](=[O:62])([O:59][CH2:60][CH3:61])[O:56][CH2:57][CH3:58])=[CH:51][CH:50]=1>CC#N>[OH:1][C:2]1[C:7]([C:8]([NH:47][CH:48]([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[C:49]2[CH:54]=[CH:53][C:52]([P:55](=[O:62])([O:56][CH2:57][CH3:58])[O:59][CH2:60][CH3:61])=[CH:51][CH:50]=2)=[O:10])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1
Reactant: CCOP(=O)(OCC)c1ccc(C(N)c2ccccc2)cc1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(=O)(OCC)c1ccc(C(NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 8-b, (309 mg, 1.5 mmol) in MeCN (10 ml) were added HATU (599 mg, 1.58 mmol), Et3N (159 mg, 1.58 mmol) and diethyl 4-(amino(phenyl)methyl)phenylphosphonate, 2-c, (479 mg, 1.5 mmol). The resulting mixture was stirred at room temperature for 2 hours. Then it was concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with sat. NH4Cl. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by prep-HPLC to provide the product, 8-1, (150 mg, 20%). 1H NMR (CD3OD, 300 MHz,): δ 10.39 (br, 1H), 8.56 (s, 1H), 8.47 (m, 1H), 7.81 (m, 1H), 7.62 (m, 2H), 7.40 (m, 2H), 7.25 (m, 5H), 6.54 (m, 1H), 6.26 (m, 1H), 3.96 (m, 4H), 1.18 (m, 6H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[CH2:12][N:13]1[CH2:17][CH2:16][C@H:15]([NH2:18])[C:14]1=[O:19].[Cl:20][C:21]1[N:26]=[C:25]2[CH:27]=[C:28]([S:30](Cl)(=[O:32])=[O:31])[S:29][C:24]2=[CH:23][CH:22]=1>>[NH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[CH2:12][N:13]1[CH2:17][CH2:16][C@H:15]([NH:18][S:30]([C:28]2[S:29][C:24]3[C:25](=[N:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[CH:27]=2)(=[O:31])=[O:32])[C:14]1=[O:19]
Reactant: O=S(=O)(Cl)c1cc2nc(Cl)ccc2s1
Reactant: N#Cc1ccc(N)c(CN2CC[C@H](N)C2=O)c1
Agent: Cl
Product: N#Cc1ccc(N)c(CN2CC[C@H](NS(=O)(=O)c3cc4nc(Cl)ccc4s3)C2=O)c1

Procedure:
The title compound is prepared from 4-amino-3-(3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-benzonitrile dihydrochloride as described in EXAMPLE 17, Part F using 5-chlorothieno[3,2-b]pyridine-2-sulfonyl chloride in place of 4,6-dichlorobenzo[b]thiophene-2-sulfonyl chloride. The crude product is purified by column chromatography eluting with a gradient of 10% EtOAc/CH2Cl2 to 25% EtOAc/CH2Cl2 to afford a white solid.
Reaction SMILES: [Na].[S:2]1([C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[NH:5]1)(=[O:4])=[O:3].[C:14]1([N:20]2[C:24](=[S:25])[N:23]([CH2:26]Cl)[N:22]=[N:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[C:14]1([N:20]2[C:24](=[S:25])[N:23]([CH2:26][N:5]3[C:6](=[O:7])[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[S:2]3(=[O:3])=[O:4])[N:22]=[N:21]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: S=c1n(CCl)nnn1-c1ccccc1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1Cn1nnn(-c2ccccc2)c1=S
Temperature: 0 °C
Yield: 58 %

Procedure:
A solution of 4.53 g (0.022 mol) of the sodium salt of saccharin and 5 g (0.022 mol) of 1-phenyl-4-chloromethyl-tetrazolin-5-thione in 50 ml of DMF was heated at 130° for four hours, then cooled and poured into ice water. The solid which separated was collected, washed with water, dried and chromatographed on silica gel, eluting with MDC, to give 4.8 g (58%) of 2-(1-phenyl-5-thioxotetrazolin-4-ylmethyl) saccharin, mp 140°-142° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.Br[CH2:16][CH2:17]Cl.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:17][CH2:16]2)=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: N#CCc1ccc(Br)cc1C(F)(F)F
Reactant: ClCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: N#CC1(c2ccc(Br)cc2C(F)(F)F)CC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 97.7 %

Procedure:
To a stirred solution of (4-bromo-2-trifluoromethyl-phenyl)-acetonitrile (3.33 g, 12.61 mmol) from step 2 of example A(141), benzyltriethylammonium chloride (0.057 g, 0.25 mmol) and 1-bromo-2-chloroethane (1.57 g, 10.94 mmol), was added dropwise a solution of NaOH 40% (3 mL). The reaction mixture was stirred 6 hours at 50° C. After this time the reaction was quenched with 1N HCl (30 mL) and extracted with EtOAC (3×30 mL). The organic phase was dried over Na2SO4 and evaporated. The crude organic product was purified by flash column chromatography (10% EtOAc in hexanes) to give the product (3.1 g, 86%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 1.4-1.44 (m, 2H), 1.76-1.80 (m, 2H), 7.44 (d, J=8.3 Hz, 1 H), 7.69 (dd, J=8.3, 2 Hz, 1 H), 7.84 (d, J=2 Hz, 1 H).
Reaction SMILES: Br[C:2]1[N:3](C2CCCCO2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][C@@H:13]([CH3:17])[CH2:14][CH2:15][CH3:16])[N:5]=2.C[O-].[Na+].[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28].[CH3:34][O:35]C1CCCC1>CC1CCCO1.CO>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[CH3:17][C@H:13]([O:12][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([O:35][CH3:34])[NH:3]2)=[C:8]([NH2:11])[N:7]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reactant: COC1CCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
8-Bromo-2-{[(1S)-1-methylbutyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.26 kg, corrected for residual solvent) was dissolved in anhydrous methyl tetrahydrofuran (MeTHF) (11.4 L) and 25% sodium methoxide in methanol (2.65 L, 3.5 eq) was added. The resultant reaction mixture was heated to 65+/−5° C. for 3 hrs. The complete reaction was cooled to room temperature and washed with 20% w/v aqueous ammonium chloride solution (2×6.3 L) and brine (6.3 L). The organic phase was dried with MgSO4 (1.8 kg) and filtered, washing through with MeTHF (6.3 L). The combined organic phases were evaporated to 6.3 L by vacuum distillation. MeOH (2.5 L) and TFA (1.26 L, 5 eq) were added and the mixture heated to 60° C. for 1.5 hours. Cyclopentyl methyl ether (CPME) (6.3 L) was added and the mixture reduced to 6.3 L by vacuum distillation. CPME (6.3 L) was again added and the reaction further concentrated to 6.3 L, when solids precipitated. The slurry was cooled to 10° C. then aged for 30 min. The product was filtered and washed with TBME (2×3.8 L) and dried in vacuo at 40° C. to afford a white solid (886 g, 74% theoretical yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.[F:20][C:21]([F:25])([F:24])[S:22]Cl.FC(F)(F)S(O)(=O)=O.ClCCCl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([S:22][C:21]([F:25])([F:24])[F:20])=[CH:11][C:12]=2[S:13]([C:16]([F:17])([F:19])[F:18])(=[O:14])=[O:15])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1cc[nH]c1-c1ccc(Cl)cc1)C(F)(F)F
Reactant: FC(F)(F)SCl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCCl
Solvent: ClCCl
Product: O=S(=O)(c1cc(SC(F)(F)F)[nH]c1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 70 °C
Yield: 72 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-[(trifluoromethyl)sulfonyl]pyrrole (2.47 g, 0.0080 mol), trifluoromethylsulfenyl chloride (2,18 g, 0,016 mol), trifluoromethanesulfonic acid (0.12 g, 0.0008 mol) and 1,2-dichloroethane (15 mL) is placed in a pressure tube, heated at 70° C. for five days, diluted with methylene chloride, washed with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain an amber syrup. Flash chromatography of the syrup using silica gel and a 1:5 ethyl acetate/hexanes solution gives the title product as an off-white solid (2.36 g, mp 118°-122° C.) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [NH:1]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C@H:2]([C:7]([NH:9][C@H:10]([C:16]([NH:18][C@H:19]([C:31]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:47]([NH:49][NH:50]C(OCC(Cl)(Cl)Cl)=O)=[O:48])[CH2:43][CH2:44][S:45][CH3:46])=[O:40])[C@H:35]([CH2:37][CH3:38])[CH3:36])=[O:32])[CH2:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[NH2:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]>CN(C=O)C.C(O)(=O)C.[Zn]>[NH:1]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C@H:2]([C:7]([NH:9][C@H:10]([C:16]([NH:18][C@H:19]([C:31]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:47]([NH:49][NH2:50])=[O:48])[CH2:43][CH2:44][S:45][CH3:46])=[O:40])[C@H:35]([CH2:37][CH3:38])[CH3:36])=[O:32])[CH2:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[NH2:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCSC)C(=O)NNC(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCSC)C(=O)NN
Reaction time: 0.67 h

Procedure:
17.9 g (17.5 mM) of Boc-Leu-Gln-Asp(OBzl)-Ile-Met-NH-NH-Troc are dissolved in a mixture of 200 ml of DMF and 50 ml of acetic acid and strongly stirred with mechanical stirring means. 11.5 g of powdered zinc (300 mesh=47 μm) are added in one operation and stirring is continued for 1 hour and 40 mins. at ambient temperature. The solid is drained, washed in DMF and the filtrate is introduced in 740 g of ice. The mixture is left to stand for one night, and then drained. The precipitate is washed with large quantities of water and dried in the open, then in a desiccator +P205.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1.[CH:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C([BH3-])#N.[Na+].[ClH:30]>O.CO>[ClH:30].[CH2:18]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:17])[C:6]1[CH:7]=[CH:8][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCC=O
Reactant: CS(=O)(=O)Nc1ccc(C(=O)NCCN)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCCNCCNC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To 1 l. of methanol is added 10.0 g (0.0389 mole) of N-(2-aminoethyl)-4-[(methylsulfonyl)amino]benzamide. The suspension is refluxed for 1 hour, then cooled. To the suspension is added 4.66 g (0.0408 mole) heptaldehyde, the mixture is then stirred over ice for 30 minutes. To the chilled mixture is added 10.26 g (0.1632 mole) of sodium cyanoborohydride. The reaction is stirred at room temperature for 24 hours, conc. HCl is added to keep the pH at about 6.0. After about 24 hours the pH of of the reaction is adjusted to pH=1.0 and reduced to 1/3 volume. 100 ml of water is added and the solid is filtered. The resultant solid is suspended in 100 ml DMF, heated to 120° C. and filtered hot. The solution is cooled and the resultant solid is filtered and dried to yield the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=C.[O:10]=[O+][O-]>CO.C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[O:10]
Reactant: O=[O+][O-]
Reactant: C=CCCCCCCBr
Solvent: CO
Solvent: ClCCl
Product: O=CCCCCCCBr
Temperature: -55 °C
Reaction time: 1 h

Procedure:
A solution of 8-bromo-1-octene (5.0 g, 0.026 mol) in 25 mL of MeOH and 5 mL of CH2Cl2 was cooled to -40° C. and treated with O3 while the mixture was cooled to -50 to -60° C. After 30 min the mixture turned bluish and after another 10 min of O3 treatment the mixture was purged with a stream of N2 for 5 min. With the mixture still at -50° C. and covered with a blanket of N2, 2.5 mL of dimethylsulfide was added. This mixture was stirred for 1 h at -40° C., 1 h at -20° C. and then allowed to warm to -10° C. over 1 h. A vacuum from the water aspiration was applied to remove some of the excess dimethylsulfide, and the residue concentrated further on a rotary evaporator (house vacuum). The residue was treated with 10 mL of water and this mixture was extracted with hexane; the organic extracts were washed with water, then brine, dried (MgSO4) and concentrated. A portion of the crude product (0.7 g) was chromatographed under pressure to give 7-bromoheptaldehyde: NMR (CDCl3) δ1.41 (m, 4H), 1.63 (m, 2H), 1.87 (m, 2H), 2.45 (m, 2H), 3.41 (m, 2H), 9.78 (s, 1H).
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:22]([OH:24])=[O:23])=[C:15]([CH3:21])[C:16]=2[N+:18]([O-:20])=[O:19])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(=O)(=O)(O)O.[CH3:30]O>>[CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:22]([O:24][CH3:30])=[O:23])=[C:15]([CH3:21])[C:16]=2[N+:18]([O-:20])=[O:19])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN1CCc2cc(C(=O)O)c(C)c([N+](=O)[O-])c21
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCCCCCCCN1CCc2cc(C(=O)OC)c(C)c([N+](=O)[O-])c21

Procedure:
1-Octyl-5-carboxy-6-methyl-7-nitroindoline (1.4 g) was dissolved in methanol (30 ml), and conc. sulfuric acid (4.1 g) was added, which was followed by refluxing for 4 hr. Methanol was evaporated under reduced pressure. Ethyl acetate (100 ml) was added to the residue. The mixture was washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=1/0-10/1) to give 750 mg of 1-octyl-5-methoxycarbonyl-6-methyl-7-nitroindoline as crystals.