Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH3:13][O:14][C:15](=[O:26])[CH:16]([NH2:25])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>>[CH3:13][O:14][C:15](=[O:26])[CH:16]([NH:25][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=1[NH2:1])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1
Reactant: COC(=O)C(N)Cc1ccc(Br)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Cc1ccc(Br)cc1)NC(=O)c1cc(Cl)ccc1N
Yield: 60 %

Procedure:
2-Amino-5-chloro-benzoic acid (0.702 g, 4.09 mmol) was coupled with 2-Amino-3-(4-bromo-phenyl)-propionic acid methyl ester hydrochloride (1 g, 4.09 mmol) using HBTU (1.86 g, 4.908 mmol) and diisopropylethylamine (1.32 ml, 10.22 mmol) as per general procedure A to yield the 2-(2-amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester in 60% yield.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].[CH3:8][C:9](O)([CH3:11])[CH3:10].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([O:7][C:9]([CH3:11])([CH3:10])[CH3:8])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: CC(C)(C)O
Reactant: C#CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
Pent-4-ynoic acid (5.0 g, 51.0 mmol), 2-methylpropan-2-ol (7.56 g, 102.0 mmol) and 4-(dimethylamino)pyridine (0.31 g, 2.54 mmol) were dissolved in DCM (17.5 ml), a solution of dicyclohexylcarbodiimide (11.6 g, 56.2 mmol) in DCM (17.5 ml) was added and the mixture was stirred at room temperature overnight. The white solid in the reaction solution was removed by filtration, after which the filtrate was washed with a 0.5 M aqueous hydrochloric acid solution and a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The residue obtained by filtration and concentration under reduced pressure was purified by silica gel column chromatography (DCM) to afford the title compound (Compound SP429) (7.15 g, 91.0%).
Reaction SMILES: [C:1](#[N:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8].CC([O-])(C)C.[K+]>O>[NH2:8][C:7]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=1[C:1]#[N:9]
Reactant: N#CCCCCCC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: N#CC1=C(N)CCCC1
Temperature: 80 °C
Yield: 74.5 %

Procedure:
A stirred mixture of 1,7-heptanedinitrile (24.44 g, 0.2 mol) and t-BuOK (22.44 g, 0.2 mol) was heated at 80° C. for 3 h under nitrogen. The mixture was then cooled down to room temperature and stored at that temperature overnight. The residue was treated with water, and extracted with ether (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by recrystallization from MeOH to give the title compound as a white solid (18.2 g, 75%). 1H NMR (400 MHz, CDCl3) δ 1.58-1.71 (m, 4H), 2.12-2.20 (m, 4H), 4.23 (bs, 2H). MS 123 (MH+).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:20]([CH3:22])([CH3:21])[O:19][C:18]([NH:23][C@H:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[N:17][S:16]2(=[O:42])=[O:41])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C(N(CC)CC)C>CO.[Pd]>[Si:28]([O:27][CH2:26][CH2:25][C@H:24]([NH:23][C:18]1[O:19][C:20]([CH3:22])([CH3:21])[CH:15]([C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=2)[S:16](=[O:42])(=[O:41])[N:17]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:31]([CH3:34])([CH3:32])[CH3:33])([CH3:30])[CH3:29]
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2)=NS(=O)(=O)C1c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2)=NS(=O)(=O)C1c1cccc(O)c1
Reaction time: 3.75 h
Yield: 87.1 %

Procedure:
Under inert gas, 1.03 g [5-(3-benzyloxyphenyl)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropyl]amine were initially charged in 20 ml of methanol and, with addition of 0.24 ml of triethylamine and 359 mg of 10% Pd/C, stirred under a hydrogen atmosphere for 3.75 hours. The completeness of the conversion was checked by LCMS, and the reaction was once again admixed with 359 mg of 10% Pd/C and stirred under a hydrogen atmosphere for a further 16 hours. According to LCMS, the detachment of the benzyl protecting group remained incomplete. After filtration to remove the solid residues, the filtrate was admixed again with 359 mg of 10% Pd/C. After stirring under a hydrogen atmosphere for 5 h, another 359 mg of 10% Pd/C were added and, after a further 2 hours, the reaction was found to be complete by checking with LCMS. After filtration to remove the catalyst residues, the filtrate was freed of the solvent under reduced pressure. This gave the product (764 mg) with a molecular weight of 518.8 g/mol (C26H38N2O5SSi); MS (ESI): m/e=519 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:12])[C:3]=1[C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1.S(Cl)(Cl)=O.Cl.[CH3:24][N:25]1[C:29]([OH:30])=[CH:28][CH:27]=[N:26]1.CC(C)(O)C#N>C1C=CC=CC=1.N1C=CC=CC=1.C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([C:27]2[CH:28]=[C:29]([OH:30])[N:25]([CH3:24])[N:26]=2)=[O:8])=[C:4]([CH3:12])[C:3]=1[C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1
Reactant: Cn1nccc1O
Reactant: Cc1cc(-c2c(C)c(C(=O)O)cc(Cl)c2Cl)on1
Agent: CC(C)(O)C#N
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(-c2c(C)c(C(=O)c3cc(O)n(C)n3)cc(Cl)c2Cl)on1
Reaction time: 2 h

Procedure:
4,5-Dichloro-2-methyl-3-(3-methylisoxazole-5-yl)benzoic acid in an amount of 0.35 g (1.2 mmol) was dissolved in 10 ml benzene, and the resulting solution was then added with thionyl chloride in an amount of 0.18 g (1.5 mmol) and one drop of pyridine and was stirred for 2 hours under heating and reflux. After distillating out the solvent from the reacted mixture under reduced pressure, the residue was dissolved in 3 ml chloroform and the resulting solution was added dropwise into a mixture of 1-methyl-5-hydroxypyrazole hydrochloride in an amount of 0. 19 g (1.4 mmol), 4 ml chloroform and triethyl amine in an amount of 0.26 g (2.6 mmol) while cooling with ice. After stirring the mixture for 30 minutes at an ambient temperature, the mixture was further added with acetone cyanohydrine in an amount of 0.03 g (0.4 mmol) and triethyl amine in an amount of 0.23 g (2.3 mmol) and was further stirred overnight at an ambient temperature. The reacted solution was washed with 1N-hydrochloric acid and then with saturated brine, then dried with anhydrous magnesium sulfate, and the solvent therein was distillated out. The obtained crystals were washed with methanol to obtain the objective compound in an amount of 0.33 g in crystalline form. Mp. 171-173° C.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH:5]1C#N)(=O)[CH3:2].F[B-](F)(F)F.[H+].[C:21]([C:27]([O:29][CH3:30])=[O:28])#[C:22][C:23]([O:25][CH3:26])=[O:24]>ClCCl.CN(C=O)C>[CH3:2][C:1]1[N:4]2[C:5]([S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=32)=[C:22]([C:23]([O:25][CH3:26])=[O:24])[C:21]=1[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CC(=O)N1c2ccccc2SC1C#N
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1c(C(=O)OC)c2sc3ccccc3n2c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-acetyl-2,3-dihydrobenzo[d]thiazole-2-carbonitrile (5 g, 24.5 mmol) in dichloromethane (50 mL) was added dropwise 7 mL of tetrafluoroboric acid (HBF4). The solution was stirred for 3 h at room temperature. The brown precipitates appeared were collected by filtration and the filter cake was washed with ether. The solid salt was added to a solution of dimethyl acetylenedicarboxylate (10.4 g, 73.0 mmol) in DMF (30 mL) and then warmed at 35° C. for 13 h. The reaction mixture was concentrated in vacuo and the residue was recrystallized from methanol to give dimethyl 1-methylbenzo[d]pyrrolo[2,1-b]thiazole-2,3-dicarboxylate, 1.7 g (23%); mp 143-144° C. 1H NMR (DMSO-d6) δ 2.85 (3H, s, Me), 3.83 (3H, s, COOMe), 3.85 (3H, s, COOMe), 7.50 (1H, t, J=7.6 Hz, ArH), 7.58 (1H, t, J=7.6 Hz, ArH), 8.07 (1H, d, J=8.0 Hz, ArH), 8.12 (1H, d, J=8.0 Hz, ArH). Anal. Calcd. for (C15H13NO4S): C, 59.39; H, 4.32; N, 4.62; S, 10.57. Found: C, 59.02; H, 4.23; N, 4.87; S, 10.42.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH:24]([CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)[C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CN1CCOCC1.Cl.[NH2:55][CH2:56][C@H:57]([NH:63][C:64]([O:66][CH2:67][C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)=[O:65])[C:58]([O:60][CH2:61][CH3:62])=[O:59]>C(OCC)(=O)C>[C:43]([O:42][C:40]([N:37]1[CH2:36][CH2:35][CH:34]([CH2:33][CH2:32][CH:24]([C:25](=[O:26])[NH:27][CH2:28][C:29](=[O:30])[NH:55][CH2:56][C@@H:57]([C:58]([O:60][CH2:61][CH3:62])=[O:59])[NH:63][C:64](=[O:65])[O:66][CH2:67][C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=2)[CH2:23][CH2:22][CH:19]2[CH2:20][CH2:21][N:16]([C:14]([O:13][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:15])[CH2:17][CH2:18]2)[CH2:39][CH2:38]1)=[O:41])([CH3:44])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(CCC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)NCC(=O)O)CC1
Reactant: CCOC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CNC(=O)CNC(=O)C(CCC1CCN(C(=O)OC(C)(C)C)CC1)CCC1CCN(C(=O)OC(C)(C)C)CC1)NC(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 90.9 %

Procedure:
Isobutyl chloroformate (13 g, 95.2 mmol) is added, at room temperature, to a solution of 2-[(4-[1-(tert-butoxycarbonyl)-4-piperidyl]-2-{2-[1-(tert-butoxycarbonyl)-4-piperidyl]ethyl}butanoyl)amino]acetic acid (compound 4) (46 g, 85.2 mmol) in 550 ml of ethyl acetate and N-methylmorpholine (19 g, 188 mmol), and a suspension is obtained. After stirring for 20 minutes, ethyl (2S)-3-amino-2-{[(benzyloxy)carbonyl]amino}propanoate hydrochloride (26.3 g, 86.9 mmol) is added. Stirring is continued for 18 hours at room temperature and the reaction medium is then washed with water, with 1N hydrochloric acid and with water and then dried over sodium sulphate and evaporated to give the crude product, which is purified by flash chromatography (20/1 dichloromethane/methanol) to give 61 g of a white solid.
Reaction SMILES: [C:1]1([C:14]2[CH:15]=[C:16](Br)[CH:17]=[C:18]([C:20]3[C:32]4[NH:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]=4[CH:23]=[CH:22][CH:21]=3)[CH:19]=2)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[B:39](OC)([O:42]C)[O:40]C.Cl>O1CCCC1>[C:1]1([C:14]2[CH:15]=[C:16]([B:39]([OH:42])[OH:40])[CH:17]=[C:18]([C:20]3[C:32]4[NH:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]=4[CH:23]=[CH:22][CH:21]=3)[CH:19]=2)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Brc1cc(-c2cccc3c2[nH]c2ccccc23)cc(-c2cccc3c2[nH]c2ccccc23)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc(-c2cccc3c2[nH]c2ccccc23)cc(-c2cccc3c2[nH]c2ccccc23)c1
Reaction time: 0.5 h

Procedure:
Under an Ar atmosphere, 3,5-dicarbazolylbromobenzene (4.87 g, 0.01 mol) and 100 mL THF (tetrahydrofuran) were added into a 250 mL single-necked flask, then 9.4 mL n-BuLi (n-butyllithium) (1.6 M n-hexane solution) was added, stirred and reacted at −78° C. for 1.5 h. After this, trimethyl borate was added and reacted for 12 h, and then 20 mL hydrochloric acid solution was added, acidified for 0.5 h. After the reaction was completed, we carried out liquid separation, drying, and concentrating under reduced pressure, and obtained 3,5-dicarbazolylphenylboronic acid by column chromatography. The reaction process is as follows:
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[N+:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41](Cl)(=[O:43])=[O:42])([O-:34])=[O:33]>C(Cl)Cl>[F:24][C:4]([F:3])([F:23])[C:5]([C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([S:41]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[N+:32]([O-:34])=[O:33])(=[O:42])=[O:43])[CH2:19][CH2:18]2)=[CH:15][CH:16]=1)([OH:10])[C:6]([F:9])([F:8])[F:7]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 0.33 h
Yield: 40.8 %

Procedure:
To a 15 mL round-bottomed flask was added 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (0.25 g, 0.62 mmol, Example 91), triethylamine (0.26 mL, 1.9 mmol) and CH2Cl2 (6 mL). To this solution at room temperature was added 2-nitrobenzenesulfonyl chloride (0.14 g, 0.62 mmol, Sigma-Aldrich, St. Louis, Mo.). The mixture was stirred for 20 min and then was concentrated onto silica gel. Purification by silica gel chromatography (0 to 6% MeOH in CH2Cl2) afforded 1,1,1,3,3,3-hexafluoro-2-(4-(4-(2-nitrophenylsulfonyl)piperazin-1-yl)phenyl)-2-propanol (0.13 g) as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[C:16]([CH3:24])[C:15]=1[O:25][CH3:26].[Cr](O)(O)(=O)=[O:28].S(=O)(=O)(O)O>>[CH3:26][O:25][C:15]1[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][C:9]#[C:8][CH2:7][CH2:6][CH2:5][C:4]#[C:3][C:2]([OH:28])=[O:1])=[C:19]([CH3:20])[C:18]([O:21][CH3:22])=[C:17]([CH3:23])[C:16]=1[CH3:24]
Reactant: COc1c(C)c(C)c(OC)c(CCCCC#CCCCC#CCO)c1C
Reactant: O=[Cr](=O)(O)O
Agent: O=S(=O)(O)O
Product: COc1c(C)c(C)c(OC)c(CCCCC#CCCCC#CC(=O)O)c1C

Procedure:
By a similar manner to Example 1, 3.56 g (10 mmoles) of 1-(12-hydroxydodeca-5,10-diynyl)-2,5-dimethoxy-3,4,6-trimethylbenzene (II: R=R1 =CH3, Y=CH2OH) was oxidized with chromic acid-sulfuric acid, whereby 12.62 g of 1,4-dimethoxy-2,3,5-trimethyl-6-(11-carboxyundeca-5,10-diynyl)benzene was obtained as an oily substance. In a mixed solvent of acetonitrile (40 ml) and water (20 ml) were dissolved 2.60 g (7.0 mmole) of the compound obtained above and 3.80 g (7.0×3 mmoles) of 2,6-dicarboxypyridine N-oxide, and the solution was stirred under cooling with ice. An ice-cooled solution of ceric ammonium nitrate (11.4 g, 7.0×3 mmoles) in 50% aqueous acetonitrile (60 ml) was added dropwise to the above solution over a period of 30 minutes, followed by stirring under the same conditions for 30 minutes and at room temperature for 30 minutes. After the completion of the reaction, insolubles were filtered out, and the acetonitrile was distilled off under reduced pressure. To the residue were added isopropyl ether (100 ml) and water (20 ml) for extraction, and the organic layer was washed with saturated sodium bicarbonate and aqueous sodium chloride, successively and dried (over MgSO4), followed by distilling off the organic solvent under reduced pressure. The residue was chromatographed on a column of silica gel developing with isopropyl ether:ethyl acetate (98:2 to 95:5) to give 2.10 g of 2,3,5-trimethyl-6-(11-carboxyundeca-5,10-diynyl)-1,4-benzoquinone. m.p. 49°-51° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1I.[C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)#[CH:18].C(N(CC)CC)C>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:18]#[C:17][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1I
Reactant: C#CC1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nccc(Cl)c1C#CC1CCCCC1
Reaction time: 8 h

Procedure:
tert-Butyl 4-chloro-3-iodopyridin-2-ylcarbamate (1.0 g, 2.82 mmol) in 10 mL tetrahydrofuran was treated with copper(I) iodide (0.027 g, 0.141 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.099 g, 0.141 mmol) and the mixture was purged with nitrogen for 5 minutes. Ethynylcyclohexane (0.472 mL, 3.67 mmol) and triethylamine (1.179 mL, 8.46 mmol) were added and the mixture was stirred overnight under nitrogen. The mixture was filtered through diatomaceous earth and the filtrate washed with aqueous citric acid (once), water (twice), and brine (once), dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography (20% ethyl acetate/hexane) provided the title compound. MS (DCI) m/e 335/337 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:18])[C@H:6]([CH2:8][S:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:7])[CH3:3].[C:19]([S:22][CH2:23][CH:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](O)=[O:26])(=[O:21])[CH3:20]>CO>[CH2:2]([O:4][C:5](=[O:18])[C@H:6]([CH2:8][S:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:7][C:25](=[O:26])[CH:24]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:23][S:22][C:19](=[O:21])[CH3:20])[CH3:3]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)[C@@H](N)CSCCc1ccccc1
Agent: Cl
Solvent: CO
Product: CCOC(=O)[C@H](CSCCc1ccccc1)NC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
React S-phenethyl-L-cysteine ethyl ester hydrochloride (2.85 g) and 3-acetylthio-2-benzylpropionic acid, (2.38 g) in a manner similar to that described in Example 1, Step 1 to give an amber oil. Chromatograph this oil on Prep 500 (2 silica gel cartridges) and elute with CH2Cl2 (4L) and then CH2Cl2 :ethyl acetate 100:2 to give Isomer A, a white solid (1.32 g), m.p. 63°-64°[α]D26 =-51.2° (MeOH); overlap Isomer A and Isomer B (0.63 g); and Isomer B, white solid (1.14 g), m.p. 84°-86°, [α]D26 =+5.3° (MeOH).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[C:12]([Cl:15])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([Si](C)(C)C)=[CH:19][C:18]=1[F:27])=[O:5])[CH3:2].[I:28]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[C:12]([Cl:15])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:28])=[CH:19][C:18]=1[F:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2c(Cl)cncc2c1Nc1ccc([Si](C)(C)C)cc1F
Reactant: ClI
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2c(Cl)cncc2c1Nc1ccc(I)cc1F
Yield: 84.1 %

Procedure:
To a solution of 7-chloro-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (0.91 g, 2.25 mmol) in dichloromethane (20 ml) at −10° C. was added iodine monochloride (4.95 ml, 4.95 mmol, 1M solution in dichloromethane) and the resultant mixture was stirred at −10° C. to 0° C. for 2 h. A saturated solution of sodium thiosulfate (25 ml) was added and the mixture was poured into saturated sodium thiosulfate (40 ml). The aqueous layer was extracted with ethyl acetate (3×35 ml) and the combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resultant residue was triturated in dichloromethane:cyclohexane 1:4 to afford the title compound as a yellow solid (0.87 g, 84%). LCMS (method B): RT=3.17 min, M+H+=460.
Reaction SMILES: [Cl:1][C:2]1[C:28]([C:29]2([C:32]#[N:33])[CH2:31][CH2:30]2)=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)[C:10]([F:23])=[CH:9][C:8]=1[F:24])=[O:5].[Cl-].[Ca+2].[Cl-].O.[OH-].[Na+]>C(O)C.[Fe].C(OCC)(=O)C>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:11]2[C:10]([F:23])=[CH:9][C:8]([F:24])=[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:25]=[CH:26][CH:27]=[C:28]([C:29]4([C:32]#[N:33])[CH2:30][CH2:31]4)[C:2]=3[Cl:1])[CH:12]=2)=[N:15][CH:16]=1
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc([N+](=O)[O-])cn4)c(F)cc3F)c2Cl)CC1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc(N)cn4)c(F)cc3F)c2Cl)CC1
Yield: 87.6 %

Procedure:
A mixed solution of 2-chloro-3-(1-cyanocyclopropyl)-N-{2,4-difluoro-5-[(5-nitropyridin-2-yl)oxy]phenyl}benzamide (5.20 g, 11 mmol), iron powder (1.24 g, 22 mmol) and calcium chloride (2.45 g, 22 mmol) in ethanol (80 mL)-water (20 mL) was stirred at 80° C. overnight. The reaction mixture was poured into 0.5N aqueous sodium hydroxide solution (500 mL), ethyl acetate (300 mL) was added, the mixture was stirred, and the insoluble material was filtered through celite. The ethyl acetate layer was separated from the filtrate, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether to give the title compound (4.25 g, 88%) as a pale-yellow amorphous.
Reaction SMILES: C(O)(=O)[C@H](CC([O-])=O)[OH:3].[Ca+2].[C:11]([OH:19])(=[O:18])[C@H:12]([CH2:14][C:15]([O-:17])=[O:16])[OH:13].S(=O)(=O)(O)O.[OH-].[K+:26].C(O)(=O)[C@H](CC(O)=O)O>O>[OH2:3].[C:11]([O-:19])(=[O:18])[C@H:12]([CH2:14][C:15]([OH:17])=[O:16])[OH:13].[K+:26]
Reactant: O=C([O-])C[C@H](O)C(=O)O
Agent: O=C(O)C[C@H](O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Solvent: O
Product: O=C(O)C[C@H](O)C(=O)[O-]
Temperature: 10 °C
Reaction time: 2 h
Yield: 140.5 %

Procedure:
207.2 g (0.5 mole) of calcium hydrogen L-malate 6 hydrate (C8H10O10.Ca.6H2O) are suspended in 300 ml of water, and 55 ml of 60% (by weight) sulfuric acid are added thereto. The precipitates of calcium sulfate are removed by filtration. The filtrate is passed through a column of about 100 ml of a cation exchange resin [manufactured by Rohm & Haas Co. under the trade name "Amberlite IR-120 (H+ type)] and then a column of about 30 ml of an anion exchange resin [manufactured by Rohm & Haas Co. under the trade name "Amberlite IR-45 (OH- type)] to remove calcium sulfate completely therefrom. 79.2 g (1.4 moles) of potassium hydroxide (purity: 85%) are added gradually to the aqueous L-malic acid solution thus obtained. Insoluble materials are removed by filtration, and the filtrate (pH 4.4) is concentrated under reduced pressure to make the total weight thereof about 300 g. The concentrated filtrate is cooled to 10° C. and the mixture (i.e., the mixture of the concentrated filtrate and crystals precipitated) is stirred at the same temperature for 2 hours. After stirring the mixture had a pH of 5.6. The crystalline precipitates are collected by filtration, washed with an aqueous 80% methanol solution and dried overnight in air at 35° C. 133.6 g of monopotassium L-malate monohydrate are obtained as crystals. Yield: 70.2% The product loses its intramolecular water at 99° to 101° C. and decomposes at 183.5° to 185° C.