Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1.CCN(C(C)C)C(C)C.[CH:23]1([CH2:26][NH2:27])[CH2:25][CH2:24]1>CCO>[CH:23]1([CH2:26][NH:27][CH2:2][C:3]2[NH:4][C:5](=[O:13])[C:6]3[CH2:12][O:11][CH2:10][CH2:9][C:7]=3[N:8]=2)[CH2:25][CH2:24]1
Reactant: NCC1CC1
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]c(CNCC2CC2)nc2c1COCC2
Temperature: 65 °C
Reaction time: 18 h
Yield: 19.6 %

Procedure:
To a solution of 2-chloromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (1 g, 5 mmol, 1 eq.) and DIEA (4.35 mL, 24.9 mmol, 5 eq.) in 7 mL of EtOH was added cyclopropylmethylamine (1.4 g, 20 mmol, 4 eq.). The resulting mixture was heated at 65° C. overnight. After 18 h, the reaction mixture was concentrated in vacuo to give an oil that was purified by silica gel column chromatography (100% CH2Cl2) to give the title compound as a white solid (0.23 g, 20%). 1H NMR (400 MHz, chloroform-d) δ ppm 4.37-4.42 (m, 2H), 3.95 (s, 1H), 3.80-3.88 (m, 3H), 2.63-2.72 (m, 1H), 2.54-2.63 (m, 3H), 0.89-1.05 (m, 1H), 0.42-0.54 (m, 2H), 0.14-0.26 (m, 2H). Exact mass calculated for C12H18N3O2 236.1. MS (ESI) m/z 236.9 (M+H)+. Retention time: 0.56 min (5-95% CH3CN/H2O over 2 min with 0.1% formic acid, Inertsil 3×3 mm C-8-3 column with flow rate of 2 mL/min).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=4)[CH:17]=3)(=[O:15])=[O:14])[C:8]2=[O:28])=[CH:4][C:3]=1[N+:31]([O-])=O.[H][H]>[Pd].CO.C(Cl)(Cl)Cl>[NH2:31][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:2]=1[NH2:1])[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28]
Reactant: [H][H]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc(N)c([N+](=O)[O-])c4)C3=O)cc2c1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc(N)c(N)c4)C3=O)cc2c1

Procedure:
10% Palladium on carbon (0.08 g) is added to a solution of 7-methoxy-naphthalene-2-sulfonic acid [1-(4-amino-3-nitrobenzyl)-2-oxopyrrolidin-3-(S)-yl]-amide (0.22 g, 0.5 mmol) (prepared as described in EXAMPLE 25, Part F) in MeOH (40 mL) and CHCl3, (3 mL) under nitrogen atmosphere. The heterogeneous mixture is hydrogenated at room temperature on a Parr apparatus under 47 p.s.i. of hydrogen for 5 hours. The catalyst is filtered and the filtrate checked by the shows no starting material. The filtrate is concentrated in vacuo and used in the subsequent step without further purification.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([NH2:10])=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[C:11](N1C=CN=C1)(N1C=CN=C1)=[O:12].C(OCC)(=O)C.Cl>O1CCCC1>[CH2:1]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:10][C:11]1=[O:12])[CH3:2]
Reactant: CCNc1ccccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCn1c(=O)[nH]c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of crude N-ethyl-benzene-1,2-diamine (8.4 g, 62 mmol) in anhydrous tetrahydrofuran (200 mL) was added 1,1′-carbonyldiimidazole (10 g, 62 mmol). The mixture was stirred at room temperature under nitrogen for 12 hours and ethyl acetate (250 mL) followed by a cold 3N aqueous solution of hydrochloric acid (200 mL) were added. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to afford 1-ethyl-1,3-dihydro-benzimidazol-2-one as a white solid (8.5 g, 69% for three steps). MS (ES) m/z 163.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH:5][C:6](=[O:26])[C@@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:8]C(OCC1C=CC=CC=1)=O.[ClH:32].[H][H]>CO.[Pd]>[ClH:32].[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH:5][C:6](=[O:26])[C@@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:8]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1ccccc1

Procedure:
A solution of 7 g. (0.016 mol) of Nα -benzyloxycarbonyl-D-phenylalanyl-L-leucine methyl ester in 120 ml. of methanol is treated with 6.12 ml. of 2.68N hydrogen chloride in methanol and reduced with hydrogen and 500 mg. of 10% palladium-on-carbon at atmospheric pressure. The reaction is monitored by thin layer chromatography. The mixture is filtered to separate the catalyst and the solution evaporated; 5.4 g. as a glass; [α]D23 -82.5° (c 1.02, methanol).
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].O[CH2:7][C:8]1[N:9]2[CH:15]=[N:14][CH:13]=[C:10]2[S:11][CH:12]=1.C(OC(C)C)(C)C>>[ClH:3].[Cl:5][CH2:7][C:8]1[N:9]2[CH:15]=[N:14][CH:13]=[C:10]2[S:11][CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1csc2cncn12
Agent: Cl
Solvent: CC(C)OC(C)C
Product: ClCc1csc2cncn12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (12.7 ml) is added to 6.67 g of 3-hydroxymethylimidazo[5,1-b]thiazole hydrochloride, and the mixture is stirred at 60° C. for 30 min. The temperature is returned to room temperature, isopropyl ether is added thereto, the supernatant is decanted, and the residue is dried under reduced pressure to give 3-chloromethylimidazo[5,1-b]thiazole hydrochloride. This compound is dissolved in 35 ml of DMF, 10.11 g of triphenylphosphine is added thereto, and the mixture is stirred at 100° C. for 12 hr. The resultant precipitate is collected by filtration to give 8.86 g of (imidazo[5,1-b]thiazol-3-yl)methyltriphenylphosphonium chloride hydrochloride.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][SH:6].[H-].[Na+].Cl[C:11]1[C:20]([CH:21]2[CH2:23][CH2:22]2)=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1.[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>CN(C)C=O>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[CH:21]1([C:20]2[C:11]([S:6][CH2:5][CH2:4][N:3]([CH3:7])[CH3:2])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:23][CH2:22]1
Reactant: CN(C)CCS
Reactant: Clc1nc2ccccc2cc1C1CC1
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: [H-]
Solvent: CN(C)C=O
Product: CN(C)CCSc1nc2ccccc2cc1C1CC1
Temperature: 0 °C

Procedure:
A solution of 2-dimethylaminoethanethiol hydrochloride (1.7 g.) in dimethylformamide (25 ml.) was added dropwise to a suspension of sodium hydride (0.5 g.) in a solution of 2-chloro-3-cyclopropylquinoline (2.0 g.) in dimethylformamide (25 ml.) at 0°-5°. The mixture was then heated at 80° for 4 hr. and then poured into ice water (200 ml.) and extracted with ethyl acetate (3×100 ml.). The ethyl acetate extract was washed successively with saturated brine (100 ml.) and water (3×100 ml.), dried (Na2SO4), and the solvent evaporated. The residue was chromatographed on silica gel (Merck 9385, 200 g.) using 10% v/v methanol in ethyl acetate as eluant. The appropriate fraction (monitored by thin layer chromatography) was evaporated, dissolved in methanol, and one equivalent of anhydrous oxalic acid was added. The solvent was evaporated and the residue crystallised from methanol/diethyl ether to give 3-cyclopropyl-2-(2-dimethylaminoethylthio)quinoline hydrogen oxalate, m.p. 158°.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8].[Li]CCCC.[C-]#[C-].[Li+].[Li+].[Br:18][C:19](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:20]=[O:21]>C1COCC1>[Br:18]/[C:19](/[CH:20]([OH:21])[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8])=[CH:22]\[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C#CCCCCC#C
Reactant: O=CC(Br)=Cc1ccccc1
Agent: [C-]#[C-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CCCCCC#CC(O)/C(Br)=C/c1ccccc1
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To a solution of 1,7-octadiyne (254.4 mg, 2.4 mmol) in dry THF (50 mL) cooled at −78° C. was added nBuLi (1.6 M in hexanes, 1.5 mL, 2.0 mmol) followed by stirring at the same temperature for 10 minutes. To the previously prepared lithium acetylide solution was added a solution of α-bromocinnamaldehyde Compound 1 (422.0 mg, 2.0 mmol) in dry THF (5 mL) and the resultant mixture was stirred at −78° C. for 15 minutes. The reaction was then quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 14 percent EtOAc in hexane) to give 613.1 mg (97 percent) of Compound 7: pale yellow oil; Rf=0.33 (14 percent EtOAc in hexane); IR (neat) 3397 (br), 3294, 2944, 2864, 2232, 2116, 1492, 1430, 1064 cm−1; 1H NMR (300 MHz, CDCl3) δ7.65-7.61 (m, 2H), 7.40-7.29 (m, 3H), 7.24 (s, 1H), 5.07 (br s, 1H), 2.68 (d, J=6.18 Hz, 1H, exchangeable with D2O), 2.34-2.27 (m, 2H), 2.26-2.19 (m, 2H), 1.96 (t, J=2.67 Hz, 1H), 1.74-1.62 (m, 4H); 13C NMR (75 MHz, CDCl3) δ135.4, 129.8, 129.1, 128.9, 126.8, 88.3, 84.8, 79.0, 69.4, 69.3, 61.2, 28.1, 27.9, 19.0, 18.6; MS (+CI) m/z (relative intensity) 318 (M+, 81Br, 4), 316 (M+, 79Br, 4), 220 (100).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)[CH2:8]1.[CH3:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>>[CH3:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:25]=1[C:26]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:10][CH2:11][CH:7]([N:3]3[CH2:4][CH2:5][CH2:6][CH:2]3[CH3:1])[CH2:8]2)=[CH:13][C:14]=1[C:19]([F:22])([F:20])[F:21])=[O:27]
Reactant: CC1CCCN1C1CCN(c2ccc(N)c(C(F)(F)F)c2)C1
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Product: Cc1ccc(C(=O)Nc2ccc(N3CCC(N4CCCC4C)C3)cc2C(F)(F)F)c(C)c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenylamine with 2,4-dimethyl benzoyl chloride. MS: 446.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:9]=1.[CH3:34][O:35][C:36]1[N:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:10]2[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:39]3[CH:40]=[N:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=3)[N:13]=[C:12]([CH3:14])[N:11]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccccc3N)n2)cc1
Reactant: COc1ccc(B(O)O)cn1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccccc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(2-aminophenyl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.54 g, 1.22 mmol), copper acetate (0.33 g, 1.83 mmol, Aldrich, St. Louis, Mo.), 6-methoxypyridin-3-ylboronic acid (0.56 g mg, 3.67 mmol, Boron Molecular, Research Triangle Park, N.C.) and diisopropylethylamine (0.85 mL, 4.89 mmol) in DCM (15 mL) was stirred at room temperature for 16 h, filtered through a pad of Celite® (diatomaceous earth), and the solvent was removed in vacuo. The crude material was adsorbed onto silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 0% to 2% 2 M NH3.MeOH in CH2Cl2, to give the title compound as a dark yellow oil. m/z (ESI, +ve ion) 548.8 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]COCC[Si](C)(C)C)=[CH:8][N:7]=1.Cl.CCOCC>CO>[CH3:21][N:2]([CH3:1])[CH2:3][C:4]#[C:5][C:6]1[N:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1
Reactant: CN(C)CC#Cc1ccc(OCOCC[Si](C)(C)C)cn1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CN(C)CC#Cc1ccc(O)cn1

Procedure:
Compound 57B (40 mg, 0.131 mmol) in MeOH (3 ml) was treated with 2 N hydrogen chloride in ether (0.1 ml, 0.200 mmol) for 1 h and the mixture was concentrated to provide the title compound 57C. LCMS (APCI) m/e 177 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[S:20][CH:21]=[CH:22][C:23]=3[CH3:24])=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.C([Si]([O:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH:51]2[CH2:53][O:52]2)=[CH:45][CH:44]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[OH:52][C@H:51]([CH2:50][O:49][C:46]1[CH:47]=[CH:48][C:43]([OH:42])=[CH:44][CH:45]=1)[CH2:53][NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([C:19]3[S:20][CH:21]=[CH:22][C:23]=3[CH3:24])=[O:18])[CH2:15][CH2:16]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccsc1C(=O)N1CCC(Sc2ccc(CCN)cc2)CC1
Product: Cc1ccsc1C(=O)N1CCC(Sc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 59.6 %

Procedure:
(4-{[4-(2-Aminoethyl)phenyl]sulfanyl}-1-piperidinyl)(3-methyl-2-thienyl)methanone (0.57 g, 1.58 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenylsilane (0.58 g, 1.44 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.656 g, 0.858 mmol).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.ClCCl.C(O)C.N>ClCCl.CO>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:1][CH2:2][CH:3]2[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2)=[O:25])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(CN)C1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOC(CNC(=O)Nc2ccc(Cl)cc2)C1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a stirred solution of tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (Prepared as described in EP 0 468231, 2.4 g) in dichloromethane (100 ml) was added 4-chlorophenylisocyanate (1.87 g). The mixture was stirred at 22° C. for 16 h before 10% 0.880 ammonia solution in methanol was added. Stirring was continued for a further 30 min before the solvent was removed in vacuo to give the title compound as a white foam (3.98 g).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[C:17]1([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([NH:16][C:28]([C:24]2[N:25]=[CH:26][O:27][C:23]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:29])[CH:13]=[N:12]1
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)CCCCn1cc(NC(=O)c2ncoc2-c2ccccc2)cn1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: ClC(OCC)=O.[CH2:7]([O:9][C:10]([C:12]1[S:13][C:14]([C:17]([OH:19])=O)=[CH:15][N:16]=1)=[O:11])[CH3:8].[N-:20]=[N+:21]=[N-:22].[Na+]>CC(C)=O.O>[N:20]([C:17]([C:14]1[S:13][C:12]([C:10]([O:9][CH2:7][CH3:8])=[O:11])=[N:16][CH:15]=1)=[O:19])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1ncc(C(=O)O)s1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1ncc(C(=O)N=[N+]=[N-])s1
Reaction time: 1 h
Yield: 75.2 %

Procedure:
Ethyl chloroformate (9.8 g, 83.6 mmol) was added to a solution of 2-(ethoxycarbonyl)thiazole-5-carboxylic acid (Intermediate X, 13 g, 64.67 mmol), TEA (9.79 g, 97.01 mmol) in acetone (130 mL) at −20° C., stirred for 1 h, then a solution of NaN3 (5.4 g, 83.6 mmol) in water (15 mL) was added and stirred at RT for 30 mins. After completion, the solvent was evaporated, the crude residue was diluted with water (150 mL) and extracted with EtOAc (2×150 mL). The combined extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered and evaporated to afford Ethyl 5-(azidocarbonyl)thiazole-2-carboxylate (11 g crude) as brown liquid. The crude was carried to next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH:14]3[CH2:17][N:16]([C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:23])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[NH:37][N:36]=[CH:35]3)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C>[CH:20]1([C:18]([N:16]2[CH2:17][CH:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:40]5[CH:39]=[C:38]6[C:34]([CH:35]=[N:36][NH:37]6)=[CH:33][CH:32]=5)=[CH:3][CH:4]=4)[C:9](=[O:23])[NH:10][N:11]=3)[CH2:15]2)=[O:19])[CH2:22][CH2:21]1
Reactant: O=C(C1CC1)N1CC(Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(C1CC1)N1CC(Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cn[nH]c4c3)cc2)C1
Temperature: 25 °C
Yield: 25.9 %

Procedure:
In a microwave vial purged with nitrogen, a mixture of 4-(4-bromophenyl)-5-{[1-(cyclopropylcarbonyl)-3-azetidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (70 mg, 0.186 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (8 mg, 9.80 μmol), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (50 mg, 0.205 mmol)) in 1,4-dioxane (2 mL) and 2M aq potassium carbonate (0.7 mL, 1.400 mmol) was stirred at 100° C. in an oil bath for 16 h. The reaction was cooled to room temperature and diluted with ethyl acetate (10 mL). The layers were separated and the aqueous layer was adjusted to pH˜6-6.5 using 1N aq HCl. The aqueous layer was extracted with ethyl acetate (2×30 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo. Purification of the residue by reverse phase HPLC (10-90% acetonitrile/water+0.1% NH4OH) provided the title compound as a white solid (20 mg, 26%). MS(ES)+ m/e 415.2 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH:25]=[C:24]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[CH:23]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])C.[OH-].[Na+]>C(O)C>[C:42]([CH2:41][CH2:40][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=3)[CH:25]=[C:24]([C:34]3[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=3)[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:47])=[O:3])([OH:44])=[O:43]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccncc3)cc(-c3ccncc3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(-c3ccncc3)cc(-c3ccncc3)c2)c1CCC(=O)O
Temperature: 52.5 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
To a solution of 4-{3-[6-(3,5-di-pyridin-4-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (195 mg, 0.3 mmol) in ethanol (10 mL) was added aqueous 1.0 N sodium hydroxide (8 mL) at room temperature. The mixture was heated to 50-55° C. and the resulting solution was stirred for 3 h. Then, the reaction mixture was concentrated and the residue was diluted with water (20 mL) and extracted with diethyl ether (50 mL) to remove any neutral impurities. The aqueous layer was acidified with 1 N hydrochloric acid until the solution become slightly acidic. The resulting white solids were collected by filtration and washed with water. After air-drying, 4-{2-(2-carboxy-ethyl)-3-[6-(3,5-di-pyridin-4-yl-phenoxy)-hexyl]-phenoxy}-butyric acid (176 mg, 99%) was isolated as a white solid: ES(+)-HRMS m/e calculated for C35H38N2O6 (M+H)+ 583.2803, found 584.2805.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1>C1(C)C=CC=CC=1.CCO.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)=[N:20][CH:21]=1
Reactant: Fc1ccc(Br)nc1
Reactant: OCc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCO
Solvent: Cc1ccccc1
Product: OCc1ccc(-c2ccc(F)cn2)cc1
Temperature: 89 °C
Reaction time: 3.33 h
Yield: 45.8 %

Procedure:
A stirred mixture of 4-(hydroxymethyl)phenylboronic acid (34) (501 mg, 3.30 mmol) and Pd(dppf)Cl2 (338 mg, 0.462 mmol) in toluene (36 mL) and EtOH (18 mL) was degassed for 15 min (vacuum pump) and then N2 was added. An aqueous solution of 2M Na2CO3 (9 mL, 18 mmol) was added by syringe and the stirred mixture was again degassed for 15 min, and then N2 was added. 2-Bromo-5-fluoropyridine (110) (1.44 g, 8.18 mmol) was added by syringe and the resulting mixture was stirred at 89° C. for 200 min. The cooled mixture was then diluted with aqueous NaHCO3 (100 mL) and extracted with CH2Cl2 (5×100 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with CH2Cl2 and 0-25% Et2O/petroleum ether firstly gave foreruns, and then further elution with 33-50% Et2O/petroleum ether gave [4-(5-fluoro-2-pyridinyl)phenyl]methanol (111) (307 mg, 46%) as a cream solid (following pentane trituration): mp 100-101° C.; 1H NMR (CDCl3) δ 8.54 (d, J=2.9 Hz, 1H), 7.94 (dt, J=8.4, 1.9 Hz, 2H), 7.72 (ddd, J=8.8, 4.2, 0.5 Hz, 1H), 7.50-7.43 (m, 3H), 4.76 (d, J=6.0 Hz, 2H), 1.69 (t, J=6.0 Hz, 1H); HRESIMS calcd for C12H11FNO m/z [M+H]+ 204.0819, found 204.0824.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][N:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([S:14]([C:13]2[C:7]3[O:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:9][C:8]=3[CH:10]=[CH:11][C:12]=2[Cl:18])(=[O:16])=[O:15])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1
Yield: 73.3 %

Procedure:
Following the general procedure for the synthesis of sulfonylamides outlined in example 51, 2-tert-butyl-6-chlorbenzooxazole-7-sulfonyl chloride (5.0 g, 16.2 mmol), triethylamine (2.4 mL, 17.2 mmol), and piperazine-carboxylic acid tert-butyl ester (3.62 g, 19.4 mmol) were reacted in THF (50 mL) to afford the title compound (5.44 g, 67%). LCMS m/z 402(M−H)+ (desired -Boc).