Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([NH:16][CH2:17][CH2:18][NH2:19])(=[O:15])=[O:14])[CH:7]=[CH:6]2.[N:20]1([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[CH:24]=[CH:23][N:22]=[CH:21]1.[C:33]([OH:36])(=O)[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([CH2:29][C:28]3[CH:31]=[CH:32][C:25]([N:20]4[CH:24]=[CH:23][N:22]=[CH:21]4)=[CH:26][CH:27]=3)[C:33](=[O:36])[CH2:34]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2
Reactant: NCCNS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: CC(=O)O
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1Cc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.8 %

Procedure:
To a solution of N-(6-chloronaphthalene-2-sulfonyl)ethylenediamine hydrochloride (321 mg) and 4-(1H-imidazol-1-yl)benzaldehyde (172 mg) in methanol (10 ml) was added acetic acid (300 mg), and the mixture was stirred at room temperature for 1 hour. To the mixture was added, under ice-cooling, sodium triacetoxyborohydride (318 mg), and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate. The solution was washed with sodium bicarbonate solution and brine, and dried, and to the solution was added triethylamine (700 mg) and then was added chloroacetyl chloride (300 mg). The mixture was stirred at room temperature for 30 minutes. The reaction solution was washed with sodium bicarbonate solution and brine, dried and concentrated. The residue was dissolved in DMF (20 ml), and to the solution was added potassium carbonate (150 mg). The mixture was stirred at 90° C. for 2 hours. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate, washed with water and brine, dried and concentrated. The residue was purified with column chromatography (ethyl acetate) and recrystallized from ethyl acetate to give colorless crystals of the title compound (177 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([C:9]#N)=[C:6]([CH:8]=1)[NH2:7].[OH-:12].[K+].[OH:14]O.Cl>O>[NH2:7][C:6]1[CH:8]=[C:2]([Cl:1])[C:3]([CH3:11])=[CH:4][C:5]=1[C:9]([OH:14])=[O:12]
Reactant: [OH-]
Reactant: Cc1cc(C#N)c(N)cc1Cl
Reactant: OO
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1cc(C(=O)O)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-chloro-2-cyano-4-methylaniline (4.0 g,0.024 mol), 30% aqueous KOH solution (56 ml), and 30% hydrogen peroxide (4 ml) was placed in an oil bath preheated to 130° C., then stirred at this temperature for 2 hours (a clear solution had obtained after 1.5 h). The clear solution was then allowed to cool to room temperature, diluted with water (200 ml), and acidified to pH ˜5.50 with 3N HCl, then allowed to stand at room temperature for few hours. The off white solid was collected by filtration, washed with water and dried in vacuo over P2O5 (4.13 g, 93%), mp 212-215° C. 1H-NMR (DMSO-d6) 2.16 (s, 3H, CH3), 6.83, 7.62 (2×s, 2H, 3-H, 6-H), 8.50 (br s, 2H, NH2); MS (FAB, m/z): 188, 186 (M+H)+; FAB-HRMS: measured: 185.0256; calculated for C8H8ClNO2 (M+) 185.0244.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16][CH2:15][CH2:14]2)[CH:3]=1.[CH2:24]([NH2:27])[CH2:25][NH2:26]>>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:13]1[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16][CH2:15][CH2:14]1)[CH:3]=[C:2]2[NH:26][CH2:25][CH2:24][NH2:27]
Reactant: NCCN
Reactant: Clc1ccc2nc(N3CCSc4ccccc4C3)cc(Cl)c2c1
Product: NCCNc1cc(N2CCSc3ccccc3C2)nc2ccc(Cl)cc12

Procedure:
The title compound was prepared in analogy to Example 4-1 in Scheme 5 by using 4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine (prepared in analogy to the one in Example 4-1) and ethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 385, 1H NMR (400 MHz, CD3OD) δ ppm 7.901 (s, 1 H), 7.70-7.60 (m, 1 H), 7.55-7.42 (m, 2 H), 7.378-3.350 (dd, J=8.8, 2.4 Hz, 1 H), 7.28-7.16 (m, 1 H), 7.14-7.12 (m, 1 H), 6.05 (s, 1 H), 5.51 (s, 1 H), 4.97 (s, 2 H), 4.38 (s, 2 H), 3.43-3.39 (t, J=6.4 Hz, 2 H), 2.99-2.95 (m, 4 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH3:24])[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[H-].[Na+].[C:29](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH3:29])[C@@:9]1([CH3:24])[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CCN(C(=O)OCc2ccccc2)C1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)[C@@]1(C)CCN(C(=O)OCc2ccccc2)C1
Reaction time: 2 h
Yield: 88 %

Procedure:
Benzyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-methylpyrrolidine-1-carboxylate (I-346) (400 mg, 1.20 mmol) and methyl iodide (112 μl, 1.79 mmol) were dissolved in dimethylformamide (12 ml), and with cooling with ice, sodium hydride (55% w/w) (62.6 mg, 1.44 mmol) was added, followed by stirring for 2 hours with cooling with ice. With cooling with ice, aqueous 10% citric acid solution was added to the reaction liquid, followed by extraction with ethyl acetate, and the obtained organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1, v/v) to obtain the entitled compound (367 mg, 88%) as a colorless oily substance.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([NH:12][C:13](=[O:23])[C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1[NH2:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N:25]1[S:29][N:28]=[C:27]2[C:30]([S:34](Cl)(=[O:36])=[O:35])=[CH:31][CH:32]=[CH:33][C:26]=12>>[N:25]1[S:29][N:28]=[C:27]2[C:30]([S:34]([NH:22][C:15]3[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=3[C:13]([NH:12][CH:4]([CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:24])=[O:23])(=[O:35])=[O:36])=[CH:31][CH:32]=[CH:33][C:26]=12
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)c1cc(Cl)c(Cl)cc1N
Product: O=C(NC(Cc1ccccc1)C(=O)O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
This compound was prepared from 2-(2-amino-4,5-dichloro-benzoylamino)-3-phenyl-propionic acid methyl ester and benzo[1,2,5]thiadiazole-4-sulfonyl chloride as in EXAMPLE 2, Parts D and E. HPLC: RT=10.10 min. MS (ESI−): mass calcd. for C22H16Cl2N4O5S2, 551.4; m/z found, 550 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.11 (s, 1H), 8.33 (dd, J=7.1, 0.9, 1H), 8.20 (dd, J=8.8, 0.8, 1H), 7.83 (s, 1H), 7.70 (dd, J=8.8, 7.1, 1H), 7.28 (m, 3H), 7.20 (s, 1H), 7.13 (dd, J=7.4, 1.7, 2H), 6.42 (d, J=7.5, 1H), 5.00 (dd, J=13.3, 6.0, 1H), 3.32 (dd, J=14.1, 5.7, 1H), 3.23 (dd, J=14.1, 6.1, 1H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[CH3:6][C:7]1([CH3:20])[C@@H:9]2[CH2:10][C:11]3[C:15]([C@H:8]12)=[C:14]([CH3:16])[S:13][C:12]=3[C:17](O)=[O:18].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.C(#N)C>[CH3:5][O:4][N:3]([CH3:2])[C:17]([C:12]1[S:13][C:14]([CH3:16])=[C:15]2[C:11]=1[CH2:10][C@H:9]1[C:7]([CH3:20])([CH3:6])[C@H:8]12)=[O:18]
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: CON(C)C(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.8 %

Procedure:
A mixture of N,O-dimehtylhydroxylamine hydrochloride (158 mg, 1.62 mmol) and (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (300 mg, 1.35 mmol) in DCM (30 mL) and acetonitrile (10 mL) is treated with diisopropylethylamine (209 mg, 1.62 mmol). To the resulting clear solution EDC.HCl (311 mg, 1.62 mmol) is added and the mixture is stirred at rt for 18 h before it is diluted with DCM (50 mL) and washed with 1 N aq. HCl (2×50 mL) and 1 N aq. NaOH (50 mL). The organic layer is dried over Na2SO4 and evaporated. The crude product is purified by prep. HPLC (Phenomenex AQUA 30×75 mm, gradient of 20-95% acetonitril in water containing 0.5% formic acid) to furnish (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid methoxy-methyl-amide (200 mg) as a pale yellow solid. LC-MS: tR=1.02 min, [M+1]+=266.04. 1H NMR (CDCl3): δ 3.75 (s, 3H), 3.29 (s, 3H), 3.12-3.01 (m, 1H), 2.93 (d, J=19.0 Hz, 1H), 2.38 (s, 3H), 1.90-1.82 (m, 2H), 1.12 (s, 3H), 0.71 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=1.C[Al](C)C.C([O:24][C:25]([C:27]1[C:36]2[C:35]3[N:37]=[CH:38][CH:39]=[CH:40][C:34]=3[CH2:33][CH2:32][CH2:31][C:30]=2[NH:29][CH:28]=1)=O)C.O>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:10][C:11]1[C:16]([NH:17][C:25]([C:27]2[C:36]3[C:35]4[N:37]=[CH:38][CH:39]=[CH:40][C:34]=4[CH2:33][CH2:32][CH2:31][C:30]=3[NH:29][CH:28]=2)=[O:24])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: CCOC(=O)c1c[nH]c2c1-c1ncccc1CCC2
Reactant: Nc1cccnc1OCCOC1CCCCO1
Agent: C[Al](C)C
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cccnc1OCCOC1CCCCO1)c1c[nH]c2c1-c1ncccc1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of 2-[2-(tetrahydropyran-2-yloxy)-ethoxy]pyridin-3-ylamine (2.3 g, 9.7 mmol) in DCM (8 mL) is added AlMe3 (2M in toluene, 4.9 mL) at rt. After stirring at room temperature for 1 h, a solution of 3,4,5,6-tetrahydro-3,10-diazabenzo[e]azulene-1-carboxylic acid ethyl ester (500 mg, 1.95 mmol) in DCM (10 mL) is added. The mixture is refluxed overnight. On cooling, water (5 mL) is added, and the resulting mixture is extracted with DCM. The combined DCM extracts are dried and solvent removed. The residue is separated by column chromatography on silica gel (5% methanol in DCM) to give 850 mg of 3,4,5,6-tetrahydro-3,10-diaza-benzo[e]azulene-1-carboxylic acid {2-[2-(tetrahydropyran-2-yloxy)-ethoxy]-pyridin-3-yl}amide as an oil.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([C@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][C@H:9]1[CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)=O)(C)(C)C.[C:31]1([C:37]2[N:41]=[C:40]([CH2:42][NH2:43])[NH:39][N:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:20][C@H:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@@H:12]1[NH:8][C@H:9]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH:43][CH2:42][C:40]3[NH:39][N:38]=[C:37]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:41]=3)=[O:27])=[CH:24][CH:23]=2)[CH2:10][CH2:11]1
Reactant: NCc1nc(-c2ccccc2)n[nH]1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1nc(-c2ccccc2)n[nH]1)c1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid (i-1, 0.020 g, 0.049 mmol) in N,N-dimethylformamide (0.5 ml) was added to 1-(3-phenyl-1H-1,2,4-triazol-5-yl)methanamine (0.018 g, 0.073 mmol) followed by 1-hydroxybenzotriazole (0.0099 g, 0.073 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (0.014 g, 0.073 mmol) and N,N-diisopropylethylamine (0.042 ml, 0.24 mmol). The reaction mixture was stirred at ambient temperature for 4 h. The mixture was directly purified by reverse phase HPLC (TMC Pro-Pac C18; 30-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). The resulting pure fractions were lyophilized overnight to give the titled compound as a white solid. LC-MS 590.2 (M+23).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([C:21]1([OH:24])[CH2:23][CH2:22]1)([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:12][CH3:13].CN1CCOCC1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)([C:21]2([OH:24])[CH2:22][CH2:23]2)[CH2:12][CH3:13])=[CH:19][CH:18]=1
Reactant: CCC(c1ccc(Cl)cc1)(n1ccc2c(N)cccc21)C1(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(c1ccc(Cl)cc1)(n1ccc2c(NS(C)(=O)=O)cccc21)C1(O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of compound from step B (83 mg, 0.22 mmol) and NMM (44 mg, 0.44 mmol) in DCM (5 mL) was added methylsulfonyl chloride (37 mg, 0.3 mmol) dropwise. Then the mixture was stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by Pre-HPLC to afford the title compound as a white solid. LC/MS m/z=419.1[M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][C:6]1[C:7](C(O)=O)=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12].[N:20]1C=CC=CC=1.C(O)(C)(C)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][C:6]1[C:7]([NH2:20])=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccnc(C(=O)O)c1Oc1cc(Cl)cc(Br)c1
Reactant: c1ccncc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccnc(N)c1Oc1cc(Cl)cc(Br)c1
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 3-(3-bromo-5-chlorophenoxy)-4-methylpyridine-2-carboxylic acid (2 g, 5.84 mmol) in THF (12 mL) was added TEA (1.627 mL, 11.68 mmol), pyridine (944 ul, 11.68 mmol), t-butanol (2.79 mL, 29.2 mmol) and diphenylphosphoryl azide (1.89 mL, 8.76 mmol). The resulting mixture was heated to 65° C. for 35 minutes, after which the mixture was diluted with CH2Cl2 (2×100 mL) and washed with water (100 mL). The combined organic extracts were concentrated in vacuo, and the resulting residue was dissolved in TFA (20 mL) and allowed to stand for 15 minutes. After this time, the solvent was removed in vacuo and the residue was partitioned between saturated aqueous NaHCO3 (50 mL) and CH2Cl2 (100 mL). The organic extract was concentrated on the rotary evaporator and the residue was purified using a RediSep column (330 g) eluting with a gradient of 0-30% EtOAc/CH2Cl2 to give the title compound. LRMS (M+1)=314.9.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](Br)=[CH:4][N:3]=1.[N:10]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[S:37](Cl)(=[O:39])=[O:38]>>[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=[CH:29][C:28]=1[S:37]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:25][C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)(=[O:18])=[O:17])=[CH:24][CH:23]=2)=[CH:4][N:3]=1)(=[O:39])=[O:38]
Reactant: O=S(=O)(c1ccc(S)cc1)N1CCOCC1
Reactant: Cc1cc(N)ncc1Br
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Product: Cc1cc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCOCC2)cc1

Procedure:
Prepared from 2-amino-5-bromo-4-methylpyridine and 4-(N -morpholinylsulfonyl)thiophenol according to General Method 11 step 1 followed by reaction with 2-chloro-4-trifluoromethylphenylsulfonyl chloride according to General Method 11 step 2. 1H NMR (CDCl3): 13.25 (1 H, br s, N11), 8.39 (1 H, s, A-ring CH ortho to Cl), 8.32 (1 H, d, J 11 Hz, A-ring CH ortho to SO2NH), 7.65 & 7.15 (2×1 H, 2×s, pyridyl CH's), 7.62 (1 H, d, J 11 Hz, A-ring CH ortho to CF3), 7.55 & 7.10 (2×2 H, 2×d, 2×J 10 Hz, Ar CH's of C-ring), 3.70-3.60 (4H, m, CH2OCH2), 2.95-2.84 (4H, m, CH2NCH2), 2.23 (3H, s, CH3). Hplc (Luna 2, Gradient 5): rt=6.01 minutes. LC/MS rt=6.75 minutes, 608 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[H-].[Na+].Cl[CH2:14][C:15]([CH3:17])=[CH2:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:15]([CH3:17])=[CH2:14])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Cl)ccc1O
Reactant: C=C(C)CCl
Agent: [H-]
Agent: [Na+]
Product: C=C(C)COc1ccc(Cl)cc1OC
Yield: 90.7 %

Procedure:
Treatment of 4-chloro-2-methoxyphenol (15.00 g, 0.10 mol) with sodium hydride (4.4 g, 0.11 mol, 60 wt. %) and 3-chloro-2-methylpropene (12.00 g, 0.12 mol) generally according to the procedure described for Intermediate 13 provided 19.3 g (91%) of 4-chloro-2-methoxy-1-[(2-methylprop-2-enyl)oxy]benzene as a colorless oil. Treatment of the allyl ether in refluxing mesitylene generally according to the procedure described for Intermediate 8 afforded 15.5 g (78%) of 4-chloro-2-methoxy-6-(2-methylprop-2-enyl)phenol as a pale yellow oil. Treatment of 4-chloro-2-methoxy-6-(2-methylprop-2-enyl)phenol (10.00 g, 0.047 mol) with 3-chloroperoxybenzoic acid (20.00 g, 0.089 mol, 77%) followed by potassium carbonate (20.00 g, 0.145 mol) generally according to the Procedure described for Intermediate 9 provided 8.00 g (74%) of (±)-(5-chloro-7-methoxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol as a light yellow oil. Treatment of (±)-(5-chloro-7-methoxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol (10.8 g, 0.047 mol) with p-toluenesulfonyl chloride (13.5 g, 0.071 mol), diisopropylethylamine (12.15 g, 0.094 mol), and 4-(dimethylamino)pyridine (0.35 g, 2.83 mmol) generally according to the procedure described for Intermediate 45 gave 13.8 g (76%) of (±)-(5-chloro-7-methoxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. mp 113-115° C.; Anal. calcd. for C18H19ClO5S: C, 56.47; H, 5.00. Found: C, 55.82; H, 4.94.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH:21]1[C:30]2[CH2:29][CH2:28][CH2:27][C:26](=[O:31])[C:25]=2[CH:24]=[CH:23][N:22]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:26]3([OH:31])[CH2:27][CH2:28][CH2:29][C:30]4[CH:21]=[N:22][CH:23]=[CH:24][C:25]3=4)=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2nccs2)cc1
Reactant: O=C1CCCc2cnccc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1(c2cnc(-c3ccc(F)cc3)s2)CCCc2cnccc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
To a solution of DIPA (0.424 g, 4.2 mmol) in dry THF at −78° C. was added n-BuLi (0.268 g, 4.2 mmol) dropwise at −78° C., and the mixture was stirred for 30 min to produce LDA. A solution of 2-(4-fluorophenyl)thiazole (0.510 g, 2.8 mmol) in dry THF at −78° C. was then added to the above LDA solution. 7,8-Dihydroisoquinolin-5(6H)-one (0.419 g, 2.8 mmol) [prepared as described in Vanotti, International Patent Publication No. WO-2008/065054] was added dropwise to the reaction mixture, which was then stirred for 20 min at −78° C. After completion of the reaction, the reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate (3×30 mL), washed with water followed by brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude solid was purified by washing with the mixture of MeOH and ether, followed by filtering resulted in 5-(2-(4-fluorophenyl)thiazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-5-ol (0.42 g, 45% yield). 1H NMR (400 MHz, DMSO-d6): δ 1.67 (m, 1H), 1.97 (m, 1H), 2.16 (t, 2H), 2.80 (t, 2H), 6.50 (s, 1H), 7.26 (s, 1H), 7.29 (m, 3H), 7.92 (m, 2H), 8.36 (m, 1H), 8.41 (s, 1H); LC-MS m/z calculated for [M+H]+ 327.09, found 327.1.
Reaction SMILES: [NH2:1][CH:2]1[CH:17]([OH:18])[CH:6]2[O:7][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:9][CH2:10][CH:5]2[CH2:4][CH:3]1[OH:19].[CH2:20]([S:22]N=C=O)C.[C:26](#[N:28])[CH3:27]>>[OH:19][C@H:3]1[C@H:2]([NH:1][C:20]([NH:28][CH2:26][CH3:27])=[S:22])[C@@H:17]([OH:18])[C@@H:6]2[O:7][C@H:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:9][CH2:10][C@H:5]2[CH2:4]1
Reactant: CCSN=C=O
Reactant: NC1C(O)CC2COC(c3ccccc3)OC2C1O
Reactant: CC#N
Product: CCNC(=S)N[C@@H]1[C@@H](O)[C@@H]2O[C@H](c3ccccc3)OC[C@H]2C[C@H]1O
Temperature: 60 °C
Yield: 100 %

Procedure:
To a suspension of the amine from above (85 mg, 0.32 mmol) in acetonitrile (3 mL) was added ethylthioisocyanate (34 mg, 0.39 mmol). The mixture was heated at 60° C. for 20 h. Solvent was evaporated to give the crude product. This was purified by silica gel chromatography, eluted with EtOAc to give pure rac-1-((2R,4aR,6R,7S,8R,8aR)-6,8-dihydroxy-2-phenylhexahydro-4H-benzo[d][1,3]dioxin-7-yl)-3-ethylthiourea (113 mg, 100%) as a white solid. 1H NMR (600 MHz, CD3OD) δ 7.52-7.50 (m, 2H), 7.40-7.31 (m, 3H), 5.60 (s, 1H), 4.15 (dd, J=10.8, 4.5, 1H), 3.69 (t, J=10.8, 1H), 3.65-3.51 (m, 5H), 1.81 (m, 2H), 1.23 (q, J=12.0, 1H), 1.20 (t, J=7.2, 1H). 13C NMR (151 MHz, CD3OD) 139.85, 129.81, 129.02, 129.03, 127.52, 102.90, 84.75, 75.14, 72.38, 71.88, 65.30, 35.21, 33.19, 14.64.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.NC1C=CC(C[C@@H:19]([C:21]([OH:23])=O)[NH2:20])=CC=1.[CH:26]([OH:29])(C)[CH3:27]>O>[OH:29][CH2:26][CH2:27][N:20]([CH2:19][CH2:21][OH:23])[C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C@@H:2]([C:10]([OH:12])=[O:11])[NH2:1])=[CH:5][CH:6]=1
Reactant: Nc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)O
Solvent: O
Product: N[C@@H](Cc1ccc(N(CCO)CCO)cc1)C(=O)O

Procedure:
About 76 g of 4-amino-L-phenylalanine obtained in Example-1 was dissolved in about 1500 mL water. Into this solution about 84 g of Ethylene oxide gas was purged over a period of about 4 hours at a temperature in the range of from about 20° C. to about 50° C. Periodically, the reaction mixture was tested by HPLC to monitor the degree of completion of the reaction as determined by the content of the in situ intermediate 4-(2-hydroxyethyl)amino)-L-phenylalanine until a level of less than about 1% 4-amino-L-phenylalanine is reached. The crude 4-(bis-(2-hydroxyethyl)amino)-L-phenylalanine was isolated by precipitation by the addition of isopropanol to the concentrated residue of the reaction mixture. The precipitated crude 4-(bis-(2-hydroxyethyl)amino)-L-phenylalanine was filtered, washed with a water-isopropanol mixture, and then dried. The purity of the crude 4-(bis-(2-hydroxyethyl)amino)-L-phenylalanine recovered was found to be about 85 to 92% by HPLC (weight, 83 g) which contains about 5 to 20% of 3-(4-(bis-(2-hydroxyethyl)amino)phenyl)-2-(2-hydroxyethylamino)-propanoic acid, and less than about 3% of 4-(2-hydroxyethyl)amino-L-phenylalanine as determined by HPLC analysis.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])=[CH:23][CH:22]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:33]([C:28]3[N:29]=[C:30]([CH3:32])[O:31][C:27]=3[C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)=[O:34])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1ccc(-c2oc(C)nc2C(=O)O)cc1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: COc1ccc(-c2oc(C)nc2C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)cc1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(4-methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid.