Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][CH:9]2[C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.[OH-].[Na+].[CH3:23][O:24]/[N:25]=[C:26](\[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37]Br)/[C:27]([O:29][CH3:30])=[O:28]>O>[S:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[CH:9]1[CH2:10][CH:8]1[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:26](=[N:25][O:24][CH3:23])[C:27]([O:29][CH3:30])=[O:28]
Reactant: CO/N=C(/C(=O)OC)c1ccccc1CBr
Reactant: Oc1cccc(C2CC2c2cccs2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CON=C(C(=O)OC)c1ccccc1COc1cccc(C2CC2c2cccs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a 20 ml glass vial equipped with a magnetic stirring bar was charged 2.2 g (0.0102 moles) of 1-(3-hydroxyphenyl)-2-(2-thienyl)cyclopropane, 15 mls of dry N,N-dimethylformamide, and 0.41 g (0.0102 moles) of powdered sodium hydroxide. To this solution was added 2.9 g (0.0102 moles) of methyl (E)-2-(bromomethyl)phenylglyoxylate O-methyloxime in one portion. The vial was capped and stirred overnight at ambient temperature. The reaction mixture was then poured into 100 mls of water, and extracted with s×100 mls of ethyl ether. The ether extract was then washed with 2×100 mls of water and 100 mls of saturated aqueous sodium chloride solution. The ether extract was then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure with a rotary evaporator at 45° C. to afford 5.1 g of the crude product as an dark green oil. This material was chromatographed on a mixed bed of neutral alumina and silica gel with 50% ethyl acetate, 50% hexane. The pure fractions were combined, and concentrated under reduced pressure with a rotary evaporator to afford 3.7 g of the title compound, Methyl2-[2-((3-(2-(thien-2-yl)cyclopropyl))phenoxymethyl)phenyl]-2-methoxyiminoacetate as a viscous yellow oil. 86% isolated yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.C(OC(=O)[N:28]([C:38]1[CH:43]=[CH:42][C:41]([CH:44]=O)=[C:40]([F:46])[N:39]=1)[CH2:29][C:30]1[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)(C)(C)C.IC1C2C(=NC=CC=2)N([Si](C(C)C)(C(C)C)C(C)C)C=1.C(OC(=O)N(CC1C(F)=CC=C(NS(CCC)(=O)=O)C=1F)C1C=CC(C=O)=CN=1)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:44][C:41]3[CH:42]=[CH:43][C:38]([NH:28][CH2:29][C:30]4[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=4)=[N:39][C:40]=3[F:46])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(Cl)cnc21
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)c(F)n2)cn1
Agent: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Agent: CCCS(=O)(=O)Nc1ccc(F)c(CN(C(=O)OC(C)(C)C)c2ccc(C=O)cn2)c1F
Product: COc1ccc(CNc2ccc(Cc3c[nH]c4ncc(Cl)cc34)c(F)n2)cn1

Procedure:
respectively, were prepared following the protocol of Scheme 178. P-0259 was prepared by replacing 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 96 with 5-chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine in Step 1 (MS [M+H+]+=506.1). P-0378 was prepared by replacing [2,6-difluoro-3-(propane-1-sulfonylamino)-benzyl]-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester 560 with (6-Fluoro-5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester 572 (prepared as described in Example 60, Scheme 177) in Step 1 (MS [M+H+]+=364.1). P-0379 was prepared by replacing both azaindole 96 with 5-chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine and aldehyde 560 with aldehyde 572 in Step 1 (MS [M+H+]+=400.0).
Reaction SMILES: BrCCO[Si](C(C)(C)C)(C)C.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].[CH3:22][C:23]1[CH:27]=[C:26]([N:28]2[CH2:32][CH2:31][NH:30][C:29]2=[O:33])[S:25][C:24]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH3:22][C:23]1[CH:27]=[C:26]([N:28]2[CH2:32][CH2:31][N:30]([CH2:13][C:14](=[O:15])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:29]2=[O:33])[S:25][C:24]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)cc1C
Reactant: O=C(CBr)c1ccccc1
Agent: CC(C)(C)[Si](C)(C)OCCBr
Product: CCOC(=O)c1sc(N2CCN(CC(=O)c3ccccc3)C2=O)cc1C
Yield: 39 %

Procedure:
Following the procedure as described in Example 50, making variations as required to replace (2-bromoethoxy)(tert-butyl)dimethylsilane with 2-bromoacetophenone to react with ethyl 3-methyl-5-(2-oxoimidazolidin-1-yl)thiophene-2-carboxylate, the title compound was obtained as a colorless solid in 39% yield: 1H NMR (300 MHz, CDCl3) δ 7.95 (d, J=8.3 Hz, 2H), 7.60-7.56 (m, 1H), 7.52-7.44 (m, 2H), 6.18 (s, 1H), 4.73 (s, 2H), 4.24 (q, J=7.1 Hz, 2H), 3.94-3.86 (m, 2H), 3.76-3.68 (m, 2H), 2.48 (s, 3H), 1.30 (t, J=7.1 Hz, 3H); MS (ES+) m/z 373.2 (M+1).
Reaction SMILES: C(OC([N:11]1[CH2:14][C@H:13]([C:15]([OH:17])=[O:16])[C@@H:12]1[C:18]([OH:20])=[O:19])=O)C1C=CC=CC=1.[H][H]>[Pd].CO>[NH:11]1[CH2:14][C@H:13]([C:15]([OH:17])=[O:16])[C@@H:12]1[C:18]([OH:20])=[O:19]
Reactant: O=C(O)[C@H]1CN(C(=O)OCc2ccccc2)[C@H]1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@H]1CN[C@H]1C(=O)O

Procedure:
cis-N-(Benzyloxycarbonyl)azetidine-2,3-dicarboxylic acid, 10% Pd/C and methanol are hydrogenated under 3 atm of hydrogen in a Parr shaker for 4 hours. The catalyst is filtered off and thoroughly washed. The solution is evaporated to dryness and dried in vacuo to arrive at cis-azetidine-2,3-dicarboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:54])[C@@H:4]([NH:19][C:20]([C@@H:22]1[CH2:35][C:34]2[CH:33]=[C:32]3[C:27]([O:28][C@@H:29]([C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=4)[C:30](=[O:37])[N:31]3[CH3:36])=[CH:26][C:25]=2[CH2:24][N:23]1[C@H:45]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:46][CH3:47])=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Cl:55][C:56]1[CH:57]=[C:58]([CH:61]=[CH:62][C:63]=1[Cl:64])[CH2:59]Br.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:54])[C@@H:4]([NH:19][C:20]([C@@H:22]1[CH2:35][C:34]2[CH:33]=[C:32]3[C:27]([O:28][C@@H:29]([C:38]4[CH:39]=[CH:40][C:41]([O:44][CH2:59][C:58]5[CH:61]=[CH:62][C:63]([Cl:64])=[C:56]([Cl:55])[CH:57]=5)=[CH:42][CH:43]=4)[C:30](=[O:37])[N:31]3[CH3:36])=[CH:26][C:25]=2[CH2:24][N:23]1[C@H:45]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[CH2:46][CH3:47])=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(Cl)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(O)cc1)O3
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(Cl)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.7 %

Procedure:
(S)-3-(4′-Chloro-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (68 mg, 0.091 mmol) was dissolved in 2 mL of DMF and 3,4-dichlorobenzyl bromide (0.46 mmol) and potassium carbonate (0.46 mmol) were added. The mixture was stirred at room temperature for 8 hours and was poured onto ethyl acetate and 10% sodium carbonate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified over silica (hexanes-ethyl acetate-MeOH, 7-3-0.1) to provide (S)-3-(4′-Chloro-biphenyl-4-yl)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (17 mg, LC/MS: m/z 903).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].[H-].[Na+].[CH:8]1([N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:15](Cl)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.O>O1CCCC1>[CH:8]1([N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:15]([NH:5][C:3]([NH:2][CH3:1])=[O:4])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(Cl)N(C1CCCCC1)C1CCCCC1
Reactant: CNC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)NC(=O)N(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 0.9 %

Procedure:
Prepared as described in General Procedure 1. To methyl urea (0.24 g) in tetrahydrofuran was added sodium hydride (22 mg of 60% in oil) and the reaction mixture stirred for 50 min at room temp. Dicyclohexyl carbamoyl chloride (0.8 g) was then added (ice bath cooling used during addition) and the mixture was stirred overnight. The reaction mixture was then added to 0.5 ml water, partially concentrated in vacuo and water (2 mL) and ethyl acetate (10 mL) was added. The non soluble material was removed by filtration and the organic layer collected and concentrated in vacuo. An aliquot of the crude was then dissolved in THF and purified by preparative LCMS to give the desired product (8 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1.[Br:12]N1C(=O)CCC1=O.CCOCC>ClC(Cl)C>[Br:12][C:9]1[CH:8]=[CH:7][C:5]2[O:6][C:2]([CH3:11])([CH3:1])[CH2:3][C:4]=2[CH:10]=1
Reactant: CC1(C)Cc2ccccc2O1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(Cl)Cl
Solvent: CCOCC
Product: CC1(C)Cc2cc(Br)ccc2O1
Temperature: 25 °C
Yield: 79 %

Procedure:
2,2-Dimethyl-2,3-dihydrobenzo[b]furan (prepared according to the method of Baker and Shulgin, J. Org. Chem., 28, 1963, 2468) (500 mg, 3.38 mmol) was taken up in dichloroethane (5.5 ml) and stirred at room temperature under nitrogen, and N-bromosuccinimide (661 mg, 3.72 mmol) added in one portion. The reaction was then refluxed for 2 h, ether was added (10 ml) and a white precipitate of succinimide filtered off. The filtrate was evaporated to dryness, and then purified by column chromatography using 5% ether in pentane as eluant to give the title product (604 mg, 79%); 1HNMR (400 MHz, CDCl3) δ: 1.43 (s, 6H), 2.92 (s, 2H), 6.54 (d, 1H), 7.16 (d, 1H), 7.19 (s, 1H); LRMS: M+H, 227. (TS+).
Reaction SMILES: Br[CH2:2][B-:3]([F:6])([F:5])[F:4].[K+:7].[CH3:8][C@@H:9]1[NH:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][N:14]([CH2:2][B-:3]([F:6])([F:5])[F:4])[C@@H:9]([CH3:8])[CH2:10]1)=[O:16])([CH3:21])([CH3:19])[CH3:20].[K+:7]
Reactant: F[B-](F)(F)CBr
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C[B-](F)(F)F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
A mixture of potassium (bromomethyl)trifluoroborate (Aldrich, 1.20 g, 5.38 mmol) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (Aldrich, 1.131 g, 5.65 mmol) in THF (7.00 mL) was heated at 80° C. under nitrogen for 24 h. The mixture was allowed to cool to ambient temperature and was then concentrated in vacuo. The residue was re-dissolved in acetone (125 mL) and treated with K2CO3 (1 eq). The suspension was stirred for 30 min and then filtered through a short plug of Celite® (diatomaceous earth). The filter cake was washed with additional acetone, and the combined organic filtrates were concentrated to give the crude product as a colorless foam (1.51 g, 88%). The pure material was obtained as a beige powder by adding acetone-ether (2:1) to the foam and then slowly adding hexanes while sonicating the mixture. 19F-NMR (377 MHz, d6-acetone) δ −141.28.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(N)cn1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(=O)(=O)c2ccc(F)cc2)cn1
Reaction time: 1 h

Procedure:
3.8 g (25 mmol) of methyl 5-amino-pyridine-2-carboxylate were dissolved in 75 ml of anhydrous pyridine, and 5.8 g (30 mmol) of 4-fluorobenzenesulfonyl chloride were added in portions, whereupon the temperature of the reaction solution rose to 35° C. After 1 hour, the mixture was concentrated in vacuo and the residue was triturated with water, filtered off with suction, washed with water and dried. This gave 7.3 g of product, melting point 183° to 185° C.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:3]=[CH:2]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:24][C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=1[S:33](Cl)(=[O:35])=[O:34]>O1CCCC1>[S:1]1[CH:5]=[C:4]([N:6]([S:33]([C:26]2[CH:27]=[C:28]([F:32])[C:29]([F:31])=[CH:30][C:25]=2[F:24])(=[O:35])=[O:34])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[N:3]=[CH:2]1
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)Nc1cscn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of tert-butyl 1,3-thiazol-4-ylcarbamate (Preparation 72, 28.94 g, 144.55 mmol) in anhydrous tetrahydrofuran (600 ml), cooled to −70° C., under nitrogen was added lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (1 M in tetrahydrofuran, 144.55 ml, 144.55 mmol) dropwise. The reaction mixture was warmed to room temperature and stirred for 1 hour before cooling −70° C. 2,4,5-trifluro benzenesulfonyl chloride (40 g, 173.46 mmol) in tetrahydrofuran (80 ml) was added dropwise and then the reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. Organic layer was washed with water and saturated aqueous sodium chloride solution before concentrating in vacuo. The crude residue was purified by column chromatography eluting with ethyl acetate:hexane (gradient 1:19 to 3:17, by volume) to afford the title compound as white solid, 37 g, 64% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[C:14]([CH2:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)#[N:15]>>[C:14]([CH2:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[N:7]=[C:6]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([CH2:16][C:14]#[N:15])=[CH:18][CH:19]=3)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=2)=[CH:19][CH:18]=1)#[N:15]
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Reactant: N#CCc1ccc(N)cc1
Product: CCOC(=O)c1cnc(Nc2ccc(CC#N)cc2)nc1Nc1ccc(CC#N)cc1

Procedure:
In like manner to N2,N4-bis(3-hydroxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine, 2,4-dichloro-5-ethoxycarbonylpyrimidine and 4-cyanomethylaniline were reacted to yield N2,N4-bis(4-cyanomethylphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.72 (s, 1H), 7.64 (m, 4H), 7.32 (d, 2H, J=8.7 Hz), 7.21 (d, 2H, J=8.4 Hz), 4.3 (q, 2H, J=7.0 Hz), 3.97 (s, 2H,), 3.89 (s, 2H), 1.32 (3H, J=7 Hz); LCMS: ret. time: 30.83 min.; purity: 90%; MS (m/e): 413 (MH+).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)(=O)C.C(OCC)(=O)C.[Pd]>[CH:1]1([CH2:6][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(=O)C2CCCC2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(CC2CCCC2)cc1OC
Yield: 98.7 %

Procedure:
A suspension of cyclopentyl(3,4-dimethoxyphenyl)methanone (10.8 g, 0.046 mol), wet Pd/C (1 g) in 10 ml of acetic acid and 10 ml of ethyl acetate was put in an autoclave at 60° C. with 20 bars of hydrogen during 24 hours. Filtration over Celite® and concentration gave 10 g of pale brown oil. This oil was purified by vacuum distillation (100-120° C., 0.02 mbar) through a short path to give 7.1 g (70%) of a colorless liquid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[NH2:51][CH:52]([C:57]1[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=1)[CH2:53][CH2:54][CH2:55][OH:56].C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:63][C:60]1[CH:59]=[CH:58][C:57]([CH:52]([NH:51][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:34][CH2:35][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:37][CH2:38]2)=[O:50])[CH2:53][CH2:54][CH2:55][OH:56])=[CH:62][CH:61]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: NC(CCCO)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CCCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (166 mg, 0.44 mmol) was added portionwise to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (150 mg, 0.42 mmol), 4-amino-4-(4-chlorophenyl)butan-1-ol (Intermediate 16) (83 mg, 0.42 mmol) and N-ethyldiisopropylamine (0.087 ml, 0.50 mmol) in DMF (2.0 mL) at 20° C. The resulting solution was stirred at 20° C. for 3 hours then quenched in water (10 ml) to give a pale yellow ppt. The precipitate was collected by filtration, washed with water and dried under vacuum to afford tert-butyl 4-(1-(4-chlorophenyl)-4-hydroxybutylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (152 mg, 67.4%) as a cream solid, which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=[O:27])[C:3]1=[O:28].[CH3:29][S:30][C:31]1[CH:38]=[CH:37][C:34](CBr)=[CH:33][CH:32]=1>>[CH3:29][S:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:1][N:2]2[C:10]3[C:5](=[CH:6][C:7]([S:11]([N:14]4[CH2:18][CH2:17][CH2:16][C@H:15]4[CH2:19][O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:12])=[O:13])=[CH:8][CH:9]=3)[C:4](=[O:27])[C:3]2=[O:28])=[CH:33][CH:32]=1
Reactant: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Reactant: CSc1ccc(CBr)cc1
Product: CSc1ccc(CN2C(=O)C(=O)c3cc(S(=O)(=O)N4CCC[C@H]4COc4ccccc4)ccc32)cc1
Yield: 64 %

Procedure:
(S)-1-(4-Methylthiobenzyl)-5-(2-phenoxymethyl-pyrrolidine-1-sulfonyl)-1H-indole-2,3-dione (11d) was prepared according to the same procedure for compound 11a, except using 4-methylthiobenzyl bromide, and purified with hexanesether (1:2) to afford 152 mg (64%) of 11d as a yellow solid, mp 175.4-176.8° C. 1H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.99 (d, J=10.5 Hz, 1H), 7.27 (m, 6H), 6.96 (t, J=7.2 Hz, 1H), 6.86 (t, J=8.1 Hz, 3H), 4.90 (s, 2H), 4.19 (d, J=8.7 Hz, 1H), 3.96 (m, 2H), 3.53 (m, 1H), 3.25 (m, 1H), 2.50 (s, 3H), 2.05 (m, 2H), 1.82 (m, 2H). Anal. Calcd for C27H26N2O5S2: C, 62.05, H, 5.01; N, 5.36. Found: C, 61.81, H, 4.95; N, 5.34.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:12]=3[C:11]2=[O:26])[CH:5]=1.C(N(CC)CC)C.[F:35][C:36]([F:41])([F:40])[C:37](O)=O>ClCCl>[CH3:25][S:24][C:21]1[N:22]=[CH:23][C:12]2[C:11](=[O:26])[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:3]4[N:27]=[C:37]([C:36]([F:41])([F:40])[F:35])[O:1][N:2]=4)[CH:5]=3)[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]=2[N:20]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(N)=NO)c1)C2=O
Reactant: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(C(F)(F)F)n3)c1)C2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
(S)—N′-Hydroxy-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzamidine (190 mg, 0.49 mmol) obtained in Step 1 of Example 75 was dissolved in dichloromethane (1.5 mL), and the mixture was cooled to 0° C. after adding triethylamine (0.14 mL, 0.99 mmol). Thereafter, anhydrous trifluoroacetic acid (0.14 mL, 0.99 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)-9-methylthio-5-[3-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenyl]-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (186 mg, 81%).
Reaction SMILES: O[C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:15][CH3:16].COCCN(CCOC)S(F)(F)[F:25]>C(Cl)Cl>[F:25][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:15][CH3:16]
Reactant: COC(=O)c1ccc(OCC(C)(C)O)c(OC)c1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC(C)(C)F)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of methyl 4-(2-hydroxy-2-methyl-propoxy)-3-methoxy-benzoate (509 mg, 2.00 mmol) in DCM (5 mL) at 0° C. was added 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-sulfanyl)ethanamine (406 μL, 2.20 mmol) dropwise. The mixture was stirred at 0° C. for 1 h before the cooling bath was removed and the mixture was stirred for 1 h at room temperature. The mixture was poured into water and was extracted with EtOAc (3×). The organics were combined, washed with water, brine, dried (Na2SO4) and evaporated to dryness. Purification of the residue by column chromatography (0-20% EtOAc in Hex) gave methyl 4-(2-fluoro-2-methyl-propoxy)-3-methoxy-benzoate (450 mg, 70%). ESI-MS m/z calc. 256.1, found 257.1 (M+1)+; Retention time: 1.57 minutes (3 min run).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[CH:10][C@H:9]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1.S(C1C(C)=CC(O)=C(C(C)(C)C)C=1)C1C(C)=CC(O)=C(C(C)(C)C)C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[C@H:10]([O:31]2)[C@H:9]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C[C@H]1C(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]2O[C@@H]2[C@H]1C(=O)OCc1ccccc1
Reaction time: 24 h

Procedure:
To a solution of (S)-2,5-dihydro-pyrrole-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (6.14 g, 20.2 mmol) were added 3-chloroperbenzoic acid (6.99 g, 40.5 mmol) and 4,4′ thiobis(6-tert-butyl-m cresol) (0.726 g, 2.02 mmol). The mixture was refluxed under nitrogen atmosphere overnight then an additional batch of 3-chloroperbenzoic acid (6.99 g, 40.5 mmol) and 4,4′ thiobis(6-tert-butyl-m cresol) (0.726 g, 2.02 mmol) was added. Refluxing was continued for 24 h. The reaction mixture was diluted with CH2Cl2, washed with sodium metabisulphite aqueous (5%), saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The diastereomeric epoxides in a ratio of 65/35 (determined by NMR on the crude mixture) were separated by flash column chromatography (c-hexane to c-hexane/EtOAc 4:1) to give (1R,2S,5S)-6-oxa-3-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-benzyl ester 3-tert-butyl ester: TLC, Rf (c-hexane/EtOAc 4:1)=0.20; MS (LC/MS): 220 [MH−Boc]+, 342 [M+Na]+; tR (HPLC conditions f): 2.14 min and (1S,2S,5R)-6-oxa-3-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-benzyl ester 3-tert-butyl ester: TLC, Rf (c-hexane/EtOAc 4:1)=0.15; MS (LC/MS): 220 [MH−Boc]+, 342 [M+Na]+; tR (HPLC conditions f): 2.03 min.