Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[C:19]([C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])(=[O:28])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[C:19]([C:29]1[CH:30]=[C:31]([NH:32][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:33]=[CH:34][CH:35]=1)(=[O:28])[CH:20]=[CH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(C(=O)C=Cc2ccccc2)c1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1COCCO1
Product: O=C(C=Cc1ccccc1)c1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (8.8 g) is added, at a temperature between 60° and 75° C., to a solution of 3-cinnamoylaniline (6.57 g) and triethylamine (5.95 g) in dioxane (165 cc) which is heated to a temperature in the vicinity of 60° C., in the course of 10 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 6 hours and 30 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. The residue is dissolved in methylene chloride (500 cc). The solution obtained is washed 4 times with distilled water (650 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. A crude product (13.5 g) is thereby obtained, which is dissolved in boiling acetonitrile (300 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 16 hours. The crystals formed are separated by filtration, washed 3 times with acetonitrile (60 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-(3- cinnamoylphenyl)-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole -7-carboxamide (7.1 g) in the form of beige-coloured crystals, m.p. 190° C., is thereby obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2O.P(Cl)(Cl)([Cl:15])=O.C(N(CC)CC)C.C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:15][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: Oc1ncnc2ccc(Cl)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Clc1ccc2ncnc(Cl)c2c1

Procedure:
Preparation D1, Step 2: 6-Chloroquinazolin-4-ol (400 mg, 2.21 mmol, 1 eq.), phosphorus oxychloride (1.99 mL, 21.4 mmol, 9.64 eq.) and triethylamine (0.99 mL, 7.11 mmol, 3.21 eq.) were mixed at room temperature under nitrogen and then refluxed for 2.5 hours. Worked up by stripping the reaction, then re-rotovapping the residue 2 times from toluene to obtain brown solids. Methylene chloride (25 mL) was added to dissolve the solids. The organic mixture was then rinsed 2 times with saturated ammonium chloride (25 mL). The organic layer was dried (sodium sulfate) and stripped to give brown solids. The solids were purified over silica gel in 9:1 to 3:1 hexanes/ethyl acetate. Obtained 4,6-dichloroquinazoline (300 mg) as an off-white solid. Yield=68%. 1H NMR (400 MHz) (DMSO-D6) δ 9.16 (s, 1H): 8.33 (s, 1H), 8.17 (apparent t, 2H, J=7 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([Cl:15])[N:8]=2)=[CH:4][C:3]=1[CH:18]=[O:19].[Br:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[CH:28]1[O:32][CH2:31][CH2:30][O:29]1.C([O-])([O-])=O.[K+].[K+].[C:39](#[N:41])[CH3:40]>>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([Cl:15])[N:8]=2)=[CH:4][C:3]=1[CH:18]1[O:27][CH2:24][CH2:23][O:19]1.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:7]2[N:8]=[C:9]([Cl:15])[CH:10]=[CH:11][C:40]=2[C:39]#[N:41])=[CH:23][C:22]=1[CH:28]1[O:29][CH2:30][CH2:31][O:32]1
Reactant: N#Cc1ccc(Oc2ccc(Br)c(C=O)c2)nc1Cl
Reactant: Oc1ccc(Br)c(C2OCCO2)c1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1ccc(Cl)nc1Oc1ccc(Br)c(C2OCCO2)c1
Product: N#Cc1ccc(Oc2ccc(Br)c(C3OCCO3)c2)nc1Cl
Temperature: 65 °C

Procedure:
To a solution of 2,6-dichloro-nicotinonitrile (3) (7.06 g, 40.8 mmol) in acetonitrile (anhydrous, 300 mL) were added 4-bromo-3-[1,3]dioxolan-2-yl-phenol (2) (10 g, 40.8 mmol) and K2CO3 (5.63 g, 40.8 mmol). The reaction was heated at 65° C. for 3 hours. The solution was filtered and evaporated in vacuo to afford 15.6 g of the product mixture. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.94 (d, J=9.0 Hz, 2H), 7.62 (d, J=8.6 Hz, 2H), 7.46 (d, J=3.1 Hz, 1H), 7.41 (d, J=3.1 Hz, 1H), 7.18-7.08 (m, 2H), 7.05 (dd, J=8.8, 2.93 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 6.11 (s, 1H), 6.09 (s, 1H), 4.19-3.99 (m, 8H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH2:32])[N:17]=[C:16]([CH:33]3[CH2:35][CH2:34]3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH:32][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])[N:17]=[C:16]([CH:33]3[CH2:34][CH2:35]3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(C2CC2)nc1OCCN
Product: CCS(=O)(=O)NCCOc1nc(C2CC2)nc(NS(=O)(=O)c2ccc(C(C)C)cn2)c1Oc1ccccc1OC

Procedure:
According to Example 39) 250 mg 5-i-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide was reacted with ethanesulfonylchloride to give 212 mg 5-i-propyl-N-[6-(2-ethanesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide. LC-MS: tR=5.18 min, [M−1]−=589.93.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:21]1([O:27][CH2:28][CH2:29][Br:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br-:30].[OH:10][C:9]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:29][CH2:28][O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH2:8][CH2:7]1)[CH2:2][CH2:3]2
Reactant: OC(c1cccs1)(c1cccs1)C12CCN(CC1)CC2
Reactant: BrCCOc1ccccc1
Product: OC(c1cccs1)(c1cccs1)C12CC[N+](CCOc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 71.5 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct -4-yl(di-2-thienyl)methanol (0.0693 g, 0.227 mmol) and 2-bromoethyl phenyl ether (0.056 g, 0.279 mmol) in 1MeOH/1CHCl3 (3.0 mL) were reacted to give the desired product (0.0822 g, 74.7%). ELMS m/z 426(M+) Rt (2.00 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20](S(C)(=O)=O)[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[O:28]1[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([C:33]([CH:30]5[CH2:31][CH2:32][O:28][CH2:29]5)=[O:34])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: O=C(O)C1CCOC1
Product: O=C(C1CCOC1)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 52 %

Procedure:
According to the procedure for compound 398 using tetrahydrofuran-3-carboxylic acid (35 mg, 0.30 mmol) afforded 22.2 mg (52% yield) of 478, as a solid.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)=[O:5].Cl[CH2:16][C:17](=O)[CH3:18].[CH3:20][NH2:21].Cl>C(Cl)Cl>[CH3:20][N:21]1[CH:16]=[C:17]([CH3:18])[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])=[C:7]1[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CN
Reactant: CC(=O)CCl
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)Cc1c(C(=O)OCC)c(C)cn1C
Reaction time: 0.07 h
Yield: 66 %

Procedure:
To a solution of 2.15 grams diethyl acetone dicarboxylate, and 1.92 grams of chloroacetone in 20 ml of methylene chloride were added 11 ml of 40 percent by weight aqueous methylamine in one portion. The temperature rose from 25° C. to 35° C. over a period of 4 to 5 minutes. The mixture was stirred without heating for 45 minutes from methylamine addition. Then 11 ml of HCl were added. The resultant product was extracted three times with chloroform and the extracts evaporated to obtain ethyl 1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate, as confirmed by gas chromatograph analysis (10% SE-52 Col. A, 100° at 10°/min.) with internal standard, in 66 percent yield and a 3 percent yield of methyl 1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetamide and 6 percent yield of ethyl 5,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate for a total of 75 percent yield of substituted pyrroles.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][NH2:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][NH:19][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=1
Reactant: COCCOCCN
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCCOCCNc1ccc([N+](=O)[O-])c(N)c1
Temperature: 120 °C
Reaction time: 72 h

Procedure:
A mixture of 5-chloro-2-nitroaniline (1.6 g, 9.3 mmol), 2-(2-methoxy-ethoxy)-ethylamine (2.0 g, 16.8 mmol) and anhydrous potassium carbonate (1.38 g, 10 mmol) in N,N-dimethylacetamide (3 ml) was stirred at 120° C. under nitrogen for 3 days. Sample NMR analysis showed 80% conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water (30 ml) and extracted with ethyl acetate. The organic extract was washed with brine, dried and evaporated. The resulting orange yellow oil was subjected to a silica gel filtration on a 5 cm×6 cm silica gel plug, eluting first with 50% ethyl acetate/petroleum spirits (40-60° C.), followed by 100% ethyl acetate. Evaporation yielded an orange-red liquid, 1.1 g (45.8% yields).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:22]([NH:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:23])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:39][CH2:40][OH:41]>O1CCCC1>[OH:41][CH2:40][CH2:39][N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:22]([NH:21][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([NH:10][C@H:1]2[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]2)[CH:20]=[CH:19]3)=[O:23])[CH2:26][CH2:27]1
Reactant: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CCNCC1
Reactant: OCCBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CCN(CCO)CC1
Temperature: 60 °C
Reaction time: 7 h
Yield: 43 %

Procedure:
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-piperidin-4-yl-urea (0.05 g, 0.12 mmol), triethylamine (0.02 mL, 0.15 mmol) and 2-bromoethanol (0.019 mL, 0.15 mmol) were dissolved in tetrahydrofuran (3 mL) and stirred at 60° C. for 7 h. The reaction mixture was evaporated. The residue was subjected to column chromatography (basic silica gel, methylene chloride/methanol 19:1, 9:1) to yield the title compound (0.023 g, 41%) as a white solid; MS: m/e=446.8 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([CH3:68])([O:10]/[N:11]=[C:12](/[C:43]1[N:44]=[C:45]([NH:48][C:49]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[S:46][CH:47]=1)\[C:13]([NH:15][CH:16]1[C:41](=[O:42])[N:18]2[C:19]([C:25]([O:27][CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[C:20]([CH2:23][Cl:24])[CH2:21][S:22][C@H:17]12)=[O:14])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:77])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([C:8]([CH3:68])([O:10]/[N:11]=[C:12](/[C:43]1[N:44]=[C:45]([NH:48][C:49]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[S:46][CH:47]=1)\[C:13]([NH:15][CH:16]1[C:41](=[O:42])[N:18]2[C:19]([C:25]([O:27][CH:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:26])=[C:20]([CH2:23][Cl:24])[CH2:21][S:22](=[O:77])[C@H:17]12)=[O:14])[CH3:9])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.33 h

Procedure:
10 g (10.3 mmol) of benzhydryl 7-[(Z)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem- 4-carboxylate was dissolved in 200 ml of methylene chloride, and 1.78 g (10.3 mmol) of m-chloroperbenzoic acid was added under cooling with ice in 10 minutes. The mixture was further stirred for 20 minutes. To the reaction solution, 40 ml of a 10% sodium thiosulfate aqueous solution was added for extraction. Then, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a powder of the above-identified compound.
Reaction SMILES: B(C1CCCCC1)[CH:2]1[CH2:7]CCC[CH2:3]1.C#CCCCC.[Zn](CC)CC.C(=O)CC.CC(O[C:33]([C@H:35](O)[C@@H:36]([OH:43])[C:37]([O:39][CH:40]([CH3:42])C)=O)=O)C>CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:42]([CH:40]1[O:39][CH:37]1[CH:36]([OH:43])[CH2:35][CH3:33])[CH2:3][CH2:2][CH3:7]
Reactant: B(C1CCCCC1)C1CCCCC1
Reactant: CC(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(C)C
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: C#CCCCC
Agent: CC[Zn]CC
Solvent: CCC=O
Product: CCCCC1OC1C(O)CC
Yield: 68 %

Procedure:
The product was prepared by General procedure T using 50 mg (0.28 mmol) Cy2BH, 32 μL (0.28 mmol) 1-hexyne, 0.39 mL (0.78 mmol, 2.0 M in hexanes) Et2Zn, 2.4 mg (0.01 mmol) (−)-MIB, 18 μL (0.25 mmol) propanal, 50 μL (0.05 mmol, 1.0 M in hexanes) Ti(OiPr)4, and 21 μL (0.10 mmol) (+)-DIPT. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound in 68% yield (27 mg, 0.17 mmol). threo-diastereomer: Colorless oil. [α]D20=−12.5 (c=0.12, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 0.88 (t, 3H, J=7.0 Hz), 0.99 (t, 3H, J=7.5 Hz), 1.31-1.41 (m, 4H), 1.48-1.62 (m, 4H), 1.76 (br s, 1H), 2.73 (br t, 1H, J=2.7 Hz), 2.96 (dt, 1H, J=5.7, 2.0 Hz), and 3.70 (m, 1H) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 9.6, 13.9, 22.5, 26.5, 28.1, 31.3, 54.9, 60.7, and 69.7 ppm; IR (neat): 3356, 2960, 2922, 2852, 2355, 2332, 1729, 1463, 1414, 1378, and 1261 cm−1; HRMS-CI m/z 141.1273 [(M−OH)+; calcd for C9H17O: 141.1279]. erythro-diastereomer: Colorless oil. [α]D20=9.2 (c=0.41, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 0.88 (t, 3H, J=7.0 Hz), 0.97 (t, 3H, J=7.5 Hz), 1.22-1.27 (m, 2H), 1.30-1.43 (m, 4H), 1.48-1.56 (m, 2H), 1.82 (br s, 1H), 2.70 (dd, 1H, J=4.9, 2.1 Hz), 2.87 (dt, 1H, J=5.6, 2.0 Hz), and 3.35 (m, 1H) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 9.7, 13.9, 22.5, 27.5, 28.0, 31.3, 56.9, 61.5, and 72.6 ppm; IR (neat): 3424, 2959, 2922, 2851, 2362, 2332, 1731, 1463, 1408, and 1373 cm−1; HRMS-CI m/z 141.1273 [(M−OH)+; calcd for C9H17O: 141.1279].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:7]=1.Br[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[CH:7]=1
Reactant: Clc1cccc(OCCBr)c1
Reactant: COC(=O)CCc1cccc(CNS(=O)(=O)c2ccccc2)c1
Product: COC(=O)CCc1cccc(CN(CCOc2cccc(Cl)c2)S(=O)(=O)c2ccccc2)c1

Procedure:
Following the procedure described in Step A of Example 2, 3-[3-(benzenesulfonylamino-methyl)-phenyl]-propionic acid methyl ester was alkylated with 1-(2-bromo-ethoxy)-3-chloro-benzene to provide the title compound of Step A. 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, 2H), 7.60-7.49 (m, 3H), 7.22 (d, 1H), 7.13 -7.06 (m, 4H), 6.88 (m, 1H), 6.60 (d, 1H), 6.52 (m, 1H), 4.42 (s, 2H), 3.88 (s, 2H), 3.65 (s, 3H), 3.47 (t, 2H), 2.87 (t, 2H), 2.54 (t, 2H).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>C1COCC1.CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[O:1][C:2]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[N:3][CH:4]=1
Reactant: c1ccc(-c2cnco2)nc1
Reactant: CCCC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)c1ncc(-c2ccccn2)o1
Reaction time: 0.33 h
Yield: 46.3 %

Procedure:
(193) A solution of 2-(oxazol-5-yl)pyridine (98 mg, 0.67 mmol) in anhydrous THF (5 mL) cooled to −75° C. under N2 was treated with n-BuLi (2.5 M in hexanes, 1.1 equiv, 0.74 mmol, 0.3 mL), and stirred for 20 min. ZnCl2 (0.5 M in THF, 2.0 equiv, 1.34 mmol, 2.7 mL) was added at −75° C., and stirred for 45 min at 0° C. Cul (1.0 equiv, 0.67 mmol, 128 mg) was added, and the solution was stirred for 10 min at 0° C. Butyryl chloride (2.0 equiv, 1.34 mmol, 143 mg, 0.14 mL) was added and the solution was stirred for 1 h at 0° C. The reaction was diluted with EtOAc (10 mL), and washed with 15% aqueous NH4OH (1×10 mL), H2O (1×10 mL), and saturated aqueous NaCl (1×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5 cm×17.5 cm, 20% EtOAc-hexanes) afforded 1-(5-(pyridin-2-yl)oxazol-2-yl)butan-1-one (193) (68 mg, 0.31 mmol, 46% yield) as a light brown powder: mp 54-55° C; 1H NMR (CDCl3, 250 MHz) d 8.65-8.62 (m, 1H), 7.85-7.78 (m, 3H), 7.31-7.26 (m, 1H), 3.07 (t, J=7.3 Hz, 2H), 1.87-1.72 (m, 2H), 1.00 (t, J=7.7 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz)d 188.4, 162.0, 157.3, 150.1, 146.3, 136.9, 126.8, 124.1, 120.3, 40.9, 17.5, 13.5; IR (KBr) umax 2963, 2933, 2872, 1675, 1469, 1426, 1387, 1227 cm−1; MALDI-FTMS (DHB) m/z 217.0968 (C12H12N2O2+H+ requires 217.0971).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7]([CH2:12][NH:13][C:14]2[N:15]=[CH:16][NH:17][C:18]=2[C:19]([NH2:21])=[O:20])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].ClCCl.C(OC(N=[C:31]=[S:32])=O)C.FC(F)(F)C(O)=O>C(O)C>[CH2:1]([O:5][C:6]1[C:7]([CH2:12][N:13]2[C:14]3[N:15]=[CH:16][NH:17][C:18]=3[C:19](=[O:20])[NH:21][C:31]2=[S:32])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccnc1CNc1nc[nH]c1C(N)=O
Reactant: CCOC(=O)N=C=S
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: CCCCOc1cccnc1Cn1c(=S)[nH]c(=O)c2[nH]cnc21
Temperature: 25 °C
Yield: 6.7 %

Procedure:
To 4-{[(3-butoxypyridin-2-yl)methyl]amino}-1H-imidazole-5-carboxamide (0.991 g, 3.43 mmol, obtained from Example 19(b)) was added dichloromethane (20 mL), ethoxycarbonyl isothiocyanate (0.47 mL, 4.11 mmol) and absolute ethanol (2 mL). After stirring o.n., more ethoxycarbonyl isothiocyanate (0.23 mL) was added and the solution was heated to reflux for 2 h upon, which more ethoxycarbonyl isothiocyanate (0.10 mL) was added and the solution was refluxed for 2 h more. The volatiles were removed in vacuo and 1 N sodium hydroxide (20 mL) was added and the suspension was heated to reflux for 4 h. After cooling to r.t. the solution was neutralized with 2 N hydrochloric acid. The resulting precipitate was filtered, washed with water and dried resulting in 0.699 g of crude product. Purification was achieved with a portion of the crude material (300 mg) by trituration with methanol and dichloromethane and then concentrating the organic layer followed by prep HPLC providing 0.103 g (16% yield, 0.231 mmol) of the title compound as its trifluoroacetic acid salt.
Reaction SMILES: [C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15]([NH:17][CH2:18][CH3:19])=[N:14][C:13]=1[CH3:20])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[SH2:21]>N1C=CC=CC=1>[C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15]([NH:17][CH2:18][CH3:19])=[N:14][C:13]=1[CH3:20])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[S:21])[NH2:2]
Reactant: CCNc1nc(C)c(C(=O)NC(C#N)c2cccs2)s1
Reactant: S
Solvent: c1ccncc1
Product: CCNc1nc(C)c(C(=O)NC(C(N)=S)c2cccs2)s1
Temperature: 60 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
0.85g of 2-ethylamino-4-methyl-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methyl)-amide (5) was dissolved in 2ml of pyridine and the reaction solution was stirred for 6 hours at 60° C. while introducing hydrogen sulfide gas. After removing the pyridine, the residue was recrystallized from ethylacetate to obtain 0.86g (Yield 91%) of the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])(=[O:7])[CH3:6]>>[C:5]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]([C:12]([Cl:3])=[O:13])[CH:10]=1)(=[O:7])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cccc(C(=O)O)c1
Product: CC(=O)Oc1cccc(C(=O)Cl)c1
Yield: 98.5 %

Procedure:
Using the above procedure, reaction of with thionyl chloride (11.1 mL, 15.3 mmol) and 3-acetoxybenzoic acid (2.50 g, 13.9 mmol) gave 511 (2.72 g, 99%) as a colorless oil. This material was used in the next step without additional purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][NH:30][CH3:31])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[C:33]1[C:41]([OH:43])=O.C(N=C=NC(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:25][CH:26]=[CH:27][N:28]=3)=[CH:20][C:19]=2[CH2:29][N:30]([CH3:31])[C:41]([C:33]2[NH:32][C:40]3[C:35]([CH:34]=2)=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:43])(=[O:11])=[O:10])[O:4][N:3]=1
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)c2cc3ccccc3[nH]2)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.2 %

Procedure:
To a solution of 0.05 g (0.114 mmol) of N-(3,4-dimethyl-5-isoxazolyl)-2'-[(methylamino)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide prepared as described in step A of Example 28 in 2 mL of CH2Cl2 and 0.1 mL DMF, 0.018 g (0.114 mmol) of indole-2-carboxylic acid and 0.021 g (0.142 mmol) of 1,3-diisopropylcarbodiimide were added. The mixture was then stirred at room temperature for 12 hr and evaporated. The residue was purified by reverse phase preparative HPLC on a 30×500 mm ODS S10 column using 80% solvent B (90% MeOH, 10% H2O, 0.1% TFA) and 20% solvent A (10% MeOH, 90% H2O, 0.1% TFA). The appropriate fractions were collected and neutralized with aqueous sodium bicarbonate to pH 7 and concentrated to 10 mL. The solution was then acidified to pH 4 using aqueous sodium bisulfate and the white solid was filtered and dried to provide 0.024 g (36%) of the title compound of this Example as a white solid. m.p. 135°-145° C.