Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[CH3:31][S:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1>>[CH3:31][S:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:16][CH2:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][NH:8][CH:12]=2)=[CH:35][CH:34]=1
Reactant: CSc1ccc(C)cc1
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Na+]
Product: CSc1ccc(COCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 5 mmol of 4-(methylthio)phenylmethane chloride are treated aa described in Example 5.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH:19]=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:29][CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O>CN(C)C=O>[Si:32]([O:31][CH2:30][CH2:29][N:20]1[C:21]2[C:17](=[CH:16][C:15]([C:13]([N:10]3[CH2:11][CH2:12][CH:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:25][CH:24]=4)[CH2:8][CH2:9]3)=[O:14])=[CH:23][CH:22]=2)[CH:18]=[CH:19]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=C(c1ccc2[nH]ccc2c1)N1CCC(Oc2ccc(Cl)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc2cc(C(=O)N3CCC(Oc4ccc(Cl)cc4)CC3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a stirred solution of (4-(4-chlorophenoxy)piperidin-1-yl)(1H-indol-5-yl)methanone (30 mg, 0.085 mmol, Step-1 of Example 353) and sodium hydride (60% in oil, 4 mg, 0.17 mmol) in N,N-dimethylformamide (1.5 mL) was added (2-bromoethoxy)(tert-butyl)dimethylsilane (24 mg, 0.10 mmol) at room temperature. After stirring at room temperature for 2 hours, the mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with water (20 mL), and dried over sodium sulfate. After removal of the solvent, the residue was purified by silica-gel column chromatography (NH-gel, eluting with ethyl acetate) to give 43 mg (>99% yield) of (1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indol-5-yl)(4-(4-chlorophenoxy)piperidin-1-yl)methanone as orange oil. This material was treated with 2M aqueous hydrochloric acid solution (0.4 mL) and tetrahydrofuran (1.5 mL) at room temperature for 1 hour. The mixture was neutralized by saturated sodium hydrogen carbonate aqueous solution and extracted with ethyl acetate (3 mL). The organic layer was dried over sodium sulfate. After removal of the solvent, the residue was purified by silica-gel column chromatography (NH-gel, eluting with ethyl acetate) and then preparative LC-MS to give 7.1 mg (18% yield) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:16]=[CH:15][C:8]([CH2:9][O:10][CH2:11][CH:12]2[CH2:14][O:13]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:17]#[C:18][NH2:19].[Na]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][CH2:11][CH:12]2[O:13][C:18]([NH2:19])=[N:17][CH2:14]2)=[CH:15][CH:16]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N#CN
Reactant: CC(C)(C)c1ccc(COCC2CO2)cc1
Agent: [Na]
Product: CC(C)(C)c1ccc(COCC2CN=C(N)O2)cc1

Procedure:
The title compound was prepared from 2-(4-tert-butyl-benzyloxymethyl)-oxirane and sodium hydrogen cyanamide according to the procedures employed for the preparation of the compound in Step 2 of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([OH:18])=O)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:26]([NH:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH3:29].O>C1(C)C=CC=CC=1>[CH2:26]([N:30]([CH2:31][CH2:32][CH2:33][CH3:34])[C:16]([C:10]1[C:11](=[O:15])[CH:12]=[C:13]([CH3:14])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]=1)=[O:18])[CH2:27][CH2:28][CH3:29]
Reactant: Cc1cc(=O)c(C(=O)O)nn1-c1ccc(Cl)cc1
Reactant: CCCCNCCCC
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(Cl)cc2)c(C)cc1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.2 %

Procedure:
To an ice cooled suspension of 5.29 g (0.02 mol) 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-6-methyl pyridazine-3-carboxylic Acid (see Example 12) and 2.02 g (0.02 mol) of triethylamine in 100 ml of toluene there is added dropwise 2.17 g (0.02 mol) of ethyl chlorofomate. The suspension formed is stirred at room temperature for 15 min. and is cooled to 5° C. To the suspension is added 2.59 g (0.02 mol) di-n-butylamine and the mixture is stirred at room temperature for 18 hrs. To the mixture is added 100 ml of water and the suspension formed is stirred at room temperature for 1 hr. The toluene layer is isolated, dried over magnesium sulfate and concentrated in vacuo. The residue oil is dissolved in 25 ml of ether and to it there is added 25 ml of hexane. The mixture is allowed to stand at room temperature for 30 minutes and is vacuum filtered. The filter cake is washed with hexane and air dried to afford 5.5 g (73% yield) of product, mp 101°-105° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][C:27]3[O:35][CH2:34][O:33][C:28]=3[CH:29]=2)[CH2:24]1>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH3:21])[CH:23]3[CH2:32][CH2:31][C:30]4[C:25](=[CH:26][C:27]5[O:35][CH2:34][O:33][C:28]=5[CH:29]=4)[CH2:24]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNC1CCc2cc3c(cc2C1)OCO3
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C1CCc3cc4c(cc3C1)OCO4)CC2

Procedure:
The title compound is prepared from 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-chloropropane and 2-methylamino-6,7-methylenedioxy-1,2,3,4-tetra-hydronaphthalene analogously to Example 1. Mp: >148° C. (decomp.).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14]1[CH:27]=[CH:26][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[C:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:8][CH2:7]2>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C@@H:10]([C:14]1[CH:27]=[CH:26][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)[C@@H:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)CCC(c1ccccc1)=C2c1ccc(OCCN2CCCC2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Yield: 93.4 %

Procedure:
A solution of 1-[2-[4-(6-methoxy-2-phenyl-3,4 dihydronaphthalen-1-yl)phenoxy]ethyl]pyrrolidine hydrochloride (nafoxidene hydrochloride) (1.0 g, 2.16 mmol) in 20 mL of absolute ethanol containing 1.0 g of palladium hydroxide on carbon was hydrogenated at 60 psi (0.41 MPa) at 20° C. for 19 hr. Filtration and evaporation provided 863 mg (93%) of cis-1-{2-[4-(6-methoxy-2-phenyl 1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy] ethyl}pyrrolidine.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10])[CH3:2].[Br-:11].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl>[Br:11][C:7]1[CH:6]=[C:5]([CH3:9])[C:4]([OH:10])=[C:3]([CH2:1][CH3:2])[CH:8]=1
Reactant: CCc1cccc(C)c1O
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)cc(C)c1O
Temperature: 0 °C
Yield: 182.7 %

Procedure:
Then, 16 g of 2-ethyl-6-methylphenol was dissolved in 200 ml of chloroform, which was stirred at 0° C., and 56.6 g of tetrabutylammonium tribromide was added in small portions to this solution. After stirring at room temperature for 1 hour, the solvent was distilled out under reduced pressure. The residue was dissolved in 300 ml of diethyl ether, successively washed with 10% hydrochloric acid and water, dried over anhydrous magnesium sulfate, and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 23 g of 4-bromo-2-ethyl-6-methylphenol (92% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[S:14][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)=[N:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[S:14][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)=[N:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1CCN(c2ncc(-c3cccc([N+](=O)[O-])c3)s2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2ncc(-c3cccc(N)c3)s2)CC1
Reaction time: 3 h
Yield: 85.7 %

Procedure:
To a solution of ethyl 1-[5-(3-nitrophenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylate (75 mg, 0.21 mmol) in ethyl acetate (1.9 mL) and acetic acid (0.19 mL) was added 10% palladium on carbon (22 mg, 0.021 mmol), and the mixture was stirred under an atmosphere of hydrogen (balloon) for 3 hours. The mixture was filtered through celite, washing with ethyl acetate and the filtrate concentrated under reduced pressure. Purification by CombiFlash (30-70% ethyl acetate:hexanes) provided 60 mg (0.18 mmol, 87% yield) of ethyl 1-[5-(3-aminophenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylate.
Reaction SMILES: [I-].[K+].[I:3]([C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])=O.C(O)(=O)C>O>[I:3][C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=Ic1cc([N+](=O)[O-])ccc1C(=O)O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc([N+](=O)[O-])cc1I
Temperature: 23 °C
Reaction time: 1 h

Procedure:
Solid potassium iodide (55 g, 0.33 mol) was added in one portion to a suspension of 2-iodosyl-4-nitro-benzoic acid I-1a (54.9 g, 0.18 mol) in water (250 ml) and glacial acetic acid (50 ml). Over the next 5-10 minutes, the solids gradually went into solution and the solution turned from off-white to red. After stirring for one hour at 23° C., gaseous sulfur dioxide was bubbled through the reaction mixture until the red color dissipated and a pale green suspension had formed. The solids were collected by filtration, co-evaporated from toluene (3×250 ml), and dried in vacuo to affort 2-iodo-4-nitrobenzoic acid I-1b (33 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[N:13]=[C:12]([N:16]([CH3:18])[CH3:17])[N:11]([CH3:19])[C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]#[CH:30]>CC(C)=O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH2:30][C:29]#[CH:28])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[N:13]=[C:12]([N:16]([CH3:17])[CH3:18])[N:11]([CH3:19])[C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: CN(C)c1nc(=O)n(-c2cc(O)c(Cl)cc2F)c(=O)n1C
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: C#CCOc1cc(-n2c(=O)nc(N(C)C)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of 2.80 g (8.90 mmol) of 3-[4-chloro-2-fluoro-5-(hydroxy)phenyl]-6-(dimethylamino)-1-methyl-1,3,5-triazine-2,4(1H,3H)-dione in 50 mL of acetone was added 1.47 g (10.7 mmol) of potassium carbonate and 1.98 mL (17.8 mmol) of an 80% solution of propargyl bromide in toluene. It was then warmed to reflux for 2 h. It was cooled to room temperature and the mixture was filtered and washed with excess ethyl acetate. The crude product was flash chromatographed over silica gel, eluting with a 3:7 v:v mixture of ethyl acetate and hexane to give 3.1 g of the title compound as a pale yellow solid, m.p.: 61°-65° C.; 1 -NMR (CDCl3, 200 MHz) ppm 7.0 (d, 1H), 4.75 (m, 2H), 3.45 (s, 3H), 3.1 (s, 6H), 2.6 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1)[CH3:2].C([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35]O)[CH2:31][CH2:30]1)(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:70]CCl>C(OC(=O)C)C>[ClH:70].[CH2:1]([C:3]1[C:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:35][CH:32]3[CH2:33][CH2:34][NH:29][CH2:30][CH2:31]3)=[CH:19][CH:20]=2)=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1)[CH3:2]
Reactant: ClCCl
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(OCC2CCNCC2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-(2-Ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-phenol (8), (0.12 g, 0.4 mmol) N-Boc-4-piperidinmethanol (0.11 g, 0.49 mmol) were dissolved in 3 ml of dichloromethane and triphenylphosphine (0.13 g, 0.49 mmol) and DIAD (0.12 g, 0.49 mmol) were added. The reaction mixture was stirred at rt for 12 h. It was then diluted with ethylacetate and the organic layer was washed with 5% aqueous NaHCO3 solution. The organic layer was washed again with brine and dried over Na2 SO4. It was then concentrated under reduced pressure and the crude product purified by chromatography to give the title compound as a white solid. Boc deprotection was performed analogously to example 3 step B.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]1[CH:39]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:39][C:31]3[N:30]([CH3:29])[C:38]4[C:33]([CH:32]=3)=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Cn1c(C=O)cc2ccccc21
Product: Cn1c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc2ccccc21

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 1-methylindole-2-carboxaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 522.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([C:26]1[C:27]([Cl:36])=[N:28][C:29]3[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:13]2)(C(C)(C)C)(C)C.F.F.F.C(N(CC)CC)C>C(#N)C>[Cl:36][C:27]1[C:26]([C:14]2[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:16]3[C:12]([CH:13]=2)=[CH:11][C:10]([CH2:9][OH:8])=[CH:18][CH:17]=3)=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(CO[Si](C)(C)C(C)(C)C)ccc21
Agent: F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(CO)ccc21

Procedure:
A solution of tert-butyl 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-(2-chloro-3-quinolinyl)-1H-indole-1-carboxylate (7-1, 2.50 g, 4.78 mmol, 1 equiv) and triethylamine trihydrofluoride (3.89 mL, 23.9 mmol, 5.00 equiv) in acetonitrile (100 mL) was heated at 50° C. for 3 hours. The reaction mixture was carefully partitioned between saturated sodium bicarbonate solution and ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated to give tert-butyl 2-(2-chloro-3-quinolinyl)-5-(hydroxymethyl)-1H-indole-1-carboxylate (7-2) as a tan foam. 1H NMR (500 MHz, CDCl3) δ 8.31 (d, 1H, J=8.5 Hz), 8.19 (s, 1H), 8.08 (d, 1H, J=8.5 Hz), 7.87 (d, 1H, J=8.1 Hz), 7.78 (br t, 1H, J=8.0 Hz), 7.63 (s, 1H), 7.62 (br t, 1H, J=8.0 Hz), 7.41 (d, 1H, J=8.5 Hz), 6.66 (s, 1H), 4.82 (d, 2H, J=4.9 Hz), 1.81 (br s, 1H), 1.27 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1I.C([Li])(C)(C)C.CCCCC.[N:20]1[C:27]([Cl:28])=[N:26][C:24](Cl)=[N:23][C:21]=1[Cl:22]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[Cl:22][C:21]1[N:20]=[C:27]([Cl:28])[N:26]=[C:24]([C:3]2[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[Cl:1])[N:23]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Clc1ccc(Cl)c(I)c1
Agent: [Li]C(C)(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: Clc1ccc(Cl)c(-c2nc(Cl)nc(Cl)n2)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
Alternatively, to a solution of 2,5-dichloro-iodobenzene (3.1 g, 11.4 mmol), hexamethylphosphoramide (6.6 ml) and tetrahydrofuran (20 ml), cooled to −78° C., was added a solution of tert-butyl lithium in pentane (1.7 M, 8.7 ml, 14.8 mmol) over 20 minutes. After stirring at −78° C. for 3 hours, a solution of cyanuric chloride (3.14 g, 17.1 mmol) in tetrahydrofuran (15 ml) was added over 15 minutes. After stirring at −78° C. for 1 hour, the mixture was warmed to −20° C. over 30 minutes. The reaction was quenched by slow addition of hydrochloric acid (1 M, 20 ml). The mixture was diluted with water (50 ml) and extracted with dichloromethane (3×40 ml). The combined extracts were washed with water (2×50 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane-hexane (3:5) to provide 2,4-dichloro-6-(2,5-dichloro-phenyl)-[1,3,5]triazine (1.98 g, 59% yield).
Reaction SMILES: C([O:14][NH:15][C:16]([CH:18]1[CH:24]([CH:25]([OH:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23][CH:22]=[CH:21][CH2:20][N:19]1[S:33]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34])=[O:17])(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[OH:14][NH:15][C:16]([CH:18]1[CH:24]([CH:25]([OH:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23][CH:22]=[CH:21][CH2:20][N:19]1[S:33]([C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=1)(=[O:35])=[O:34])=[O:17]
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(C(O)c3ccccc3)C2C(=O)NOC(c2ccccc2)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N2CC=CCC(C(O)c3ccccc3)C2C(=O)NO)cc1
Temperature: 12.5 °C

Procedure:
A solution of 3-(hydroxy-phenyl-methyl)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid benzhydryloxy-amide (5 mg, 0.008 mmoL) in dichloromethane (1 mL) was cooled to 0° C. This solution was treated with trifluoroacetic acid (0.1 mL) followed by a 0.31 M solution of triethylsilane in dichloromethane (0.026 mL). The reaction mixture was warmed from 0 to 25° C. over 35 minutes and then the solvents were removed in vacuo and the residue was coevaporated with toluene. The residue was purified by flash chromatography (silica, 5 to 10% methanol in dichloromethane) to give 3-(hydroxy-phenyl-methyl)-1(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid hydroxyamide as a white solid; MS: (M-H)- 430.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].Cl[C:11]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:12].C(OCC)(=O)C>O1CCCC1>[CH3:17][O:16][CH2:15][CH2:14][O:13][C:11]([NH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6])=[O:12]
Reactant: COCCOC(=O)Cl
Reactant: Nc1cccc(CO)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOC(=O)Nc1cccc(CO)c1
Reaction time: 0.5 h

Procedure:
To a solution of 15.0 g of 3-aminobenzyl alcohol in 120 ml of tetrahydrofuran was added dropwise a solution of 18 ml of 2-methoxyethyl chloroformate in 70 ml of tetrahydrofuran under ice-cooling. After stirred for 30 minutes under ice-cooling and then at room temperature for 30 minutes, additional 2 ml of 2-methoxyethyl chloroformate was added, and the mixture was stirred at room temperature for 1 hour. After ethyl acetate was added, the mixture was washed successively with an aqueous saturated sodium bicarbonate solution and then an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated to obtain 30.2 g of 3-[(2-methoxyethoxy)carbonylamino]benzyl alcohol.
Reaction SMILES: P([O-])([O-])([O-])=O.[OH:6][CH:7]1[O:26][C@H:25]([CH2:27][OH:28])[C@@H:12]([O:13][C@@H:14]2[O:22][C@H:21]([CH2:23][OH:24])[C@H:19]([OH:20])[C@H:17]([OH:18])[C@H:15]2[OH:16])[C@H:10]([OH:11])[C@H:8]1[OH:9].C([O-])([O-])=[O:30].[Ca+2:33].C(O)C1[O:40]C(O)C(O)C(O)C1O>O>[CH2:23]([OH:24])[C@H:21]1[O:22][C@@H:14]([O:13][C@@H:12]([C@H:10]([OH:11])[C@@H:8]([OH:9])[C:7]([O-:26])=[O:6])[C@H:25]([OH:30])[CH2:27][OH:28])[C@H:15]([OH:16])[C@@H:17]([OH:18])[C@H:19]1[OH:20].[CH2:23]([OH:24])[C@H:21]1[O:22][C@@H:14]([O:13][C@@H:12]([C@H:10]([OH:11])[C@@H:8]([OH:9])[C:7]([O-:26])=[O:6])[C@H:25]([OH:40])[CH2:27][OH:28])[C@H:15]([OH:16])[C@@H:17]([OH:18])[C@H:19]1[OH:20].[Ca+2:33]
Reactant: O=C([O-])[O-]
Reactant: OCC1OC(O)C(O)C(O)C1O
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: O=C([O-])[C@H](O)[C@@H](O)[C@H](O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)[C@H](O)CO

Procedure:
In 5 L of a 10 mM phosphate buffer solution (pH 7.0) containing 1000 g of lactose and 825 g of CaCO3, 200 g of GRINGAMYL SURE BAKE 800 (manufactured by DANISCO, a recombinant enzyme of marine algae-origin hexose oxidase) was suspended to give a liquid reaction mixture. This liquid reaction mixture was allowed to react under stirring and aerating (blowing air at a rate of 0.5 times by volume as much as the liquid reaction mixture per minute) for 2 days at 30° C. Then, the liquid reaction mixture was centrifuged (10,000 rpm, 30 minutes at 4° C.) to thereby remove CaCO3. The obtained supernatant was supplied into an active carbon column (5 cm (diameter)×40 cm) having been equilibrated with deionized water and eluted with 1500 ml of deionized water. The eluate was collected, concentrated to 300 mL under reduced pressure and then precipitated by adding ethanol 2.3 times as much. The precipitate was dried under reduced pressure to thereby give 1020 g of calcium lactobionate.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[SH:12]([O:15]Cl)(=O)=[O:13].[Cl:17]CCl>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12]([Cl:17])(=[O:15])=[O:13])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCCc2ccccc21
Reactant: ClCCl
Reactant: O=[SH](=O)OCl
Product: CN1CCCc2ccc(S(=O)(=O)Cl)cc21
Temperature: 25 °C
Yield: 8 %

Procedure:
A solution of 1-methyl-1,2,3,4-tetrahydroquinoline (10 g, 68.03 mmol) in dichloromethane (20 mL) was added dropwise to HSO3Cl (80 g, 689.66 mmol) at 0-5° C., and the resulting solution was maintained at room temperature overnight. The reaction mixture was then quenched by adding 300 mL of iced water. The resulting solution was extracted using ethyl acetate (3×150 mL). The organic layers were combined, concentrated, and the residue was purified by column chromatography using a 1:20 ethyl acetate/petroleum ether solvent system to afford 1-methyl-1,2,3,4-tetrahydroquinoline-7-sulfonyl chloride as a yellow liquid in 8% yield. 1H NMR (CDCl3) δ 7.19 (d, 1H), 7.10 (d, 1H), 7.06 (s, 1H), 3.33 (t, 2H), 2.97 (s, 3H), 2.81 (d, 2H), 1.99 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([Cl:10])[CH:3]=1.[C-:11]#[N:12].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[C:4]([Cl:10])[CH:3]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: N#CCc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 122.9 %

Procedure:
To a magnetically stirring solution of 4-bromo-1-bromomethyl-2-chloro-benzene (3.59 g, 12.67 mmol) from step 2 above and tetrabutylammonium bromide (0.41 g, 1.27 mmol) in CH2Cl2/H2O 1:1 (60.0 mL), was added a solution of KCN (2.48 g, 38.01 mmol) in H2O (30 mL). The resulting orange mixture was stirred at room temperature for 3 hours. The layers of the resulting reaction mixture were separated and the organic layer was washed with NaHCO3 sat solution (3×50 mL), then dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (30% EtOAc in Hexanes) to yield the intermediate as a clear oil (3.59 g, 100%). 1H NMR (400 MHz, CDCl3): δ 3.79 (s, 2H), 7.37-7.60 (m, 3H).