Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15](/[CH:21]=[CH:22]/[C:23]3([C:29]([OH:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[CH:16][CH:17]=2)[N:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.CC1C=CC=C([N+]([O-])=O)C=1C(OC(=O)C1C([N+]([O-])=O)=CC=CC=1C)=O.[Cl:66][C:67]([Cl:91])([Cl:90])[CH2:68][O:69][C:70]([C@@H:72]1[CH2:77][CH2:76][CH2:75][N:74]([C:78](=[O:89])[C@@H:79]([NH:81][C:82](=[O:88])[C@@H:83](O)[CH:84]([CH3:86])[CH3:85])[CH3:80])[NH:73]1)=[O:71]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:90][C:67]([Cl:66])([Cl:91])[CH2:68][O:69][C:70]([C@@H:72]1[CH2:77][CH2:76][CH2:75][N:74]([C:78](=[O:89])[C@@H:79]([NH:81][C:82](=[O:88])[C@@H:83]([O:30][C:29]([C:23]2(/[CH:22]=[CH:21]/[C:15]3[CH:14]=[C:13]4[C:18]([CH:19]=[CH:20][C:11]([C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:10])=[N:12]4)=[CH:17][CH:16]=3)[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[O:31])[CH:84]([CH3:85])[CH3:86])[CH3:80])[NH:73]1)=[O:71]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc2ccc(/C=C/C3(C(=O)O)CCCCO3)cc2n1
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](OC(=O)C1(/C=C/c2ccc3ccc([C@@H](C)NC(=O)OC(C)(C)C)nc3c2)CCCCO1)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 17.4 %

Procedure:
A solution of 2-{(E)-2-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-vinyl}-tetrahydro-pyran-2-carboxylic acid (135 mg, 0.3 mmol), N,N-diisopropylethylamine (96 mg, 0.133 mL, 0.75 mmol), 4-dimethylaminopyridine (80 mg, 0.66 mmol) and 2-methyl-6-nitrobenzoic anhydride (193 mg, 0.56 mmol) in dichloromethane (5 mL) was stirred at 0° C. under nitrogen. A solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (142 mg, 0.33 mmol) in dichloromethane (2 mL) was added and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with dichloromethane and the solution was washed with ice-cold saturated sodium hydrogen carbonate solution, water, ice-cold hydrochloric acid (1 M), water and brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 3:1 to 1:3 to afford the title compound (44 mg, 17%) as a white solid and as a 1:1 mixture of two diastereoisomers. LCMS (m/z) 840.2, 842.0 [M+H], Tr=3.75 min.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1C=C2C(NC(NC2=CC=1)=O)=O.O=P(Cl)(Cl)Cl.Cl.[NH2:31][S:32]([C:35]1[CH:42]=[CH:41][C:38]([CH2:39]N)=[CH:37][CH:36]=1)(=[O:34])=[O:33].C(N(C(C)C)CC)(C)C>C(O)C>[Cl:1][C:2]1[N:11]=[C:10]([CH2:39][C:38]2[CH:37]=[CH:36][C:35]([S:32]([NH2:31])(=[O:34])=[O:33])=[CH:42][CH:41]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: Cl
Agent: O=c1[nH]c(=O)c2ccccc2[nH]1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1ccc(Cc2nc(Cl)nc3ccccc23)cc1
Yield: 88 %

Procedure:
A mixture of 2,4-dichloroquinazoline [prepared from benzoyleneurea and POCl3 by the method of Butler et al., J. Chem. Soc. 1959, 1512.] (100 mg, 0.502 mmol, 1 eq), 4-aminosulfonylbenzylamine hydrochloride (117.5 mg, 0.527 mmol, 1.05 eq) and diisopropylethylamine (0.26 mL, 1.506 mmol, 3 eq) in absolute ethanol (1.6 mL) was stirred at ambient temperature for 4 h. The precipitated solid was collected by filtration, washed with water and cold ethanol, and dried to afford 154 mg (88%) of 2-chloro-4-(4-aminosulfonylbenzyl)quinazoline as a white solid. LC/MS: 349 [M+H]+; HPLC: 96% at 1.86 min (Primesphere 5 μm C18 column 4.6×30 mm, 10–90% aqueous methanol over 2 min containing 0.2% phosphoric acid, 5 mL/min, monitoring at 254 nm); 1H NMR (400 MHz, DMSO-d6): δ 9.37 (t, J=5.8 Hz, 1 H), 8.32 (d, J=8.2 Hz, 1 H), 7.85–7.53 (m, 7 H), 7.32 (s, 2 H), 4.81 (d, J=5.7 Hz, 2 H).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@:6]([NH:26]C(=O)C)([CH3:25])[CH2:7][CH2:8][C:9]1[O:10][C:11]([C:14]#[C:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].O1CCCC1.CO.[OH2:37].[OH-:38].[Li+]>O>[C:2]([OH:38])(=[O:37])[C:1]([OH:4])=[O:3].[NH2:26][C@:6]([CH3:25])([CH2:7][CH2:8][C:9]1[O:10][C:11]([C:14]#[C:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:12][CH:13]=1)[CH2:5][OH:4]
Reactant: [OH-]
Reactant: O
Reactant: CC(=O)N[C@](C)(CCc1ccc(C#CCOc2ccc(Cl)cc2)o1)COC(C)=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@](N)(CO)CCc1ccc(C#CCOc2ccc(Cl)cc2)o1
Product: O=C(O)C(=O)O
Temperature: 50 °C
Reaction time: 4 h
Yield: 137.5 %

Procedure:
To a solution of (2R)-1-acetoxy-2-acetylamino-2-methyl-4-{5-[3-(4-chlorophenyloxy)prop-1-ynyl]furan-2-yl}butane (0.3083 g, 0.74 mmol) obtained in Example (22c) in a mixed solvent of tetrahydrofuran (1.5 ml) and methanol (1.5 ml) were added successively water (1.5 ml) and lithium hydroxide monohydrate (0.3096 g, 7.38 mmol), and the resulting mixture was stirred at 50° C. for 4 hours. After cooling, water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a basic silica gel column (NH type) using a mixed solvent of dichloromethane and methanol (50:1) as the eluent to afford the crude (2R)-2-amino-2-methyl-4-{5-[3-(4-chlorophenyloxy)prop-1-ynyl]furan-2-yl}butan-1-ol (0.2156 g).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=[O:8])=[CH:3][CH:2]=1.[CH2:12]([C:19]1([C:25]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[ClH:32].[C:33]([N:41]1[CH2:46][CH2:45][CH2:44][C:43]([C:63]2[CH:68]=[CH:67][C:66]([Cl:69])=[C:65]([Cl:70])[CH:64]=2)([CH2:47][CH2:48][CH2:49][N:50]2[CH2:55][CH2:54][CH:53]([C:56]([N:58]3[CH2:62][CH2:61][CH2:60][CH2:59]3)=[O:57])[CH2:52][CH2:51]2)[CH2:42]1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.O>[OH2:8].[ClH:69].[C:33]([N:41]1[CH2:46][CH2:45][CH2:44][C:43]([CH2:47][CH2:48][CH2:49][N:22]2[CH2:23][CH2:24][C:19]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])[CH2:20][CH2:21]2)([C:63]2[CH:68]=[CH:67][C:66]([Cl:69])=[C:65]([Cl:70])[CH:64]=2)[CH2:42]1)(=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1.[C:33]([N:41]1[CH2:46][CH2:45][CH2:44][C:43]([C:63]2[CH:68]=[CH:67][C:66]([Cl:69])=[C:65]([Cl:70])[CH:64]=2)([CH2:47][CH2:48][CH2:49][N:50]2[CH2:51][CH2:52][C:53]([C:56]([N:58]3[CH2:59][CH2:60][CH2:61][CH2:62]3)=[O:57])([CH2:11][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:54][CH2:55]2)[CH2:42]1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[ClH:32]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(N1CCCC1)C1(Cc2ccccc2)CCNCC1
Reactant: O=C(c1ccccc1)N1CCCC(CCCN2CCC(C(=O)N3CCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1CCCC(CCCN2CCC(Cc3ccccc3)(C(=O)N3CCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 80 °C

Procedure:
A mixture of 4-benzyl-4-(pyrrolidin-1-ylcarbonyl)piperidine p-toluene-sulfonate, 0.65 g of the compound obtained in step B of EXAMPLE 1 and 0.7 g of K2CO3 in 6 ml of DMF is heated at 80° C. for 3 hours. The reaction mixture is poured into iced water and the precipitate formed is filtered off and washed with water. The precipitate is dissolved in AcOEt, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (95/5; v/v) as the eluent. The product obtained is taken up with ethereal hydrogen chloride and the precipitate formed is filtered off to give 0.56 g of the expected product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:9]([CH:18]=[O:19])[NH:8][C:7]=1[CH2:20][CH2:21][NH:22]C(OC(C)(C)C)=O)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:9]([CH:18]=[O:19])[NH:8][C:7]=1[CH2:20][CH2:21][NH2:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CCNC(=O)OC(C)(C)C)[nH]c(C=O)c1-c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1c(CCN)[nH]c(C=O)c1-c1ccc(F)cc1
Reaction time: 2 h

Procedure:
A stirred solution of 2-(2-tert-butoxycarbonylamino-ethyl)-4-(4-fluoro-phenyl)-5-formyl-1H-pyrrole-3-carboxylic acid ethyl ester (1.02 g, 2.5 mmol) in dichloromethane (25 ml) was added dropwise slowly with trifluoroacetic acid (2.5 ml) at room temperature. Upon completion of the addition, the mixture was stirred for 2 hours, and concentrated to give 2-(2-amino-ethyl)-4-(4-fluoro-phenyl)-5-formyl-1H-pyrrole-3-carboxylic acid ethyl ester which was used as such.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH2:15]([O:17][C:18](=[O:41])[CH2:19][O:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28](=O)[NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=1)[CH3:16]>N1C=CC=CC=1.O.C(OCC)(=O)C>[CH2:15]([O:17][C:18](=[O:41])[CH2:19][O:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28](=[S:2])[NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=1)[CH3:16]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOC(=O)COc1cc(F)ccc1C(=O)NCc1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)COc1cc(F)ccc1C(=S)NCc1cccc([N+](=O)[O-])c1
Temperature: 115 °C
Yield: 176.8 %

Procedure:
In a flame dried flask under a nitrogen atmosphere, a suspension of phosphorus pentasulfide (0.77 g, 1.73 mmol) in pyridine (6.9 mL) was treated with [5-fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid ethyl ester (Example 27, 1.3 g, 3.45 mmol) and heated to 115° C. for 4 h. After cooling to room temperature, the mixture was diluted with water and ethyl acetate. The organic layer was washed successively with 2 N HCl and saturated NaCl, dried over MgSO4, and concentrated. The dark orange solid was filtered through a short pad of silica and again concentrated to give [5-fluoro-2-(3-nitro-benzylthiocarbamoyl)-phenoxy]-acetic acid ethyl ester as an orange solid (1.2 g, 89%): mp 118° C.; Rf 0.43 (40% ethyl acetate in heptane); 1H NMR (DMSO-d6 300 MHz) δ 10.71 (s, 1H), 8.23 (s, 1H), 8.12 (d, J=8.1 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.71-7.60 (m, 2H), 7.04 (dd, J1=11.1 Hz, J2=2.4 Hz, 1H), 6.87 (dt, J1=8.4 Hz, J2=2.4 Hz, 1H), 5.07 (d, J=3.3 Hz, 2H), 4.89 (s, 2H), 4.13 (q, J=6.7 Hz, 2H), 1.17 (t, J=5.7 Hz, 3H). ESI-LC/MS m/z calcd for C18H17FN2O5S: 394.1. Found 393.0 (M+1)+. Anal. calcd for C18H17FN2O5S: C, 55.09; H, 4.37; N, 7.14. Found C, 54.98; H, 4.36; N, 7.08.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+].F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>C(#N)C.O>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([N:2]2[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]2)=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: O=C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.4 %

Procedure:
To 4-piperidone hydrochloride (2.17 g, 16.0 mmol) in acetonitrile (20 ml) was added triethylamine (3.9 ml) and potassium carbonate (2.9 g, 21.0 mmol). After stirring for 20 min at room temperature, 1-fluoro-4-nitrobenzene (1 g, 7.09 mmol) was added and the reaction mixture was heated to reflux for 12 hr. The reaction mixture was then cooled and filtered and the filtrate concentrated under reduced pressure to give a residue. The residue was dissolved in water, extracted with ethyl acetate, dried and evaporated to give 1-(4-nitro-phenyl)-piperidin-4-one (0.6 g, 38%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:11]=[C:12]([OH:18])[C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)([O-:9])=[O:8].Cl.ClC[CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.[C:28](OCC)(=O)C>CN(C=O)C.O>[CH3:28][O:18][C:12]1[CH:11]=[C:10]([N+:7]([O-:9])=[O:8])[CH:15]=[CH:14][C:13]=1[O:16][CH2:17][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: CCOC(C)=O
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCCC1
Temperature: 100 °C

Procedure:
Potassium carbonate (3.3 g) was added to a solution of 4-nitroguaiacol (1.0 g) and 1-(2-chloroethyl)pyrrolidine hydrochloride (1.0 g) in DMF (20.0 mL), and the mixture was heated at 100° C. overnight. The reaction mixture was then mixed with ethyl acetate and water, and the organic phase was washed twice with water, dried over sodium sulfate and concentrated. The product with the molecular weight of 266.3 (C13H18N2O4) was obtained in this way; MS (ESI): 267 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=2.[CH3:16][C:17]([CH3:22])([CH2:20]O)[CH:18]=[O:19]>CO>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:14][CH3:15])[N:4]=[CH:3][C:2]([NH:1][CH2:16][C:17]([CH3:22])([CH3:20])[CH2:18][OH:19])=[CH:11]2
Reactant: CC(C)(C=O)CO
Reactant: COc1cc2cc(N)cnc2cc1OC
Solvent: CO
Product: COc1cc2cc(NCC(C)(C)CO)cnc2cc1OC
Yield: 21.5 %

Procedure:
The reaction is run similar to the preparation in Example 11. To a MeOH solution of 4 Å powdered molecular sieves (0.35 g) under argon is added 3-amino-6,7-dimethoxyquinoline (0.32 g, 1.6 mmol) and 2,2-dimethyl-3-hydroxypropionaldehyde (0.19 g, 1.9 mmol). The product mixture is chromatographed (3% MeOH/CHCl3) to afford 0.10 g of material which is partitioned between CH2Cl2/10% NaOH. The organic layer is washed with 10% NaOH, H2O, and brine, then dried (MgSO4), and recrystallized from EtOAc/hexanes to provide a light-orange solid (m.p. 170-173.5° C). Anal. Calcd. for C16H22N2O3: C, 66.18; H, 7.64; N, 9.65; Found: C, 66.11; H, 7.49; N, 9.33.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])OC(Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:53]=1[CH:59]([NH2:61])[CH3:60]>C(Cl)(Cl)Cl>[F:51][C:52]1[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:53]=1[CH:59]([NH:61][C:43]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)=[CH:8][C:2]=1[F:1])=[O:49])[CH3:60]
Reactant: COc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1OCCCN1CCOCC1
Reactant: CC(N)c1ccc(F)cc1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2c(Oc3ccc(NC(=O)NC(C)c4ccc(F)cc4F)c(F)c3)ccnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 82.9 %

Procedure:
2-Fluoro-4-{[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy}-aniline (30 mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml) to prepare a solution. A solution of triphosgene (17 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 25 min. Next, a solution of 1-(2,4-difluorophenyl)ethylamine (14 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 5 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (29 mg, yield 66%).
Reaction SMILES: [CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][NH2:7])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:18]([O:25]C(Cl)=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:29]([O-])([O-])=[O:30].[K+].[K+]>C(Cl)Cl.CCOCC>[CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[C:5](=[C:29]=[O:30])[CH2:6][NH:7][O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N(CCN)C(C)C
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(C(=C=O)CNOCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropyl-ethylenediamine (4.94 gm, 0.034 mol) was dissolved in CH2Cl2 (20 mL) and cooled to 0° C. under nitrogen. Triethylamine (4.7 mL) and benzyloxycarbonyl chloride (4.9 mL) were then added and the mixture was stirred overnight while being allowed to reach room temperature. The mixture was then poured into Et2O (250 mL) and K2CO3 was added. This mixture was then washed successively with H2O and brine and the pooled aqueous layers were back-extracted with Et2O. The pooled organic layers were dried over Na2SO4, filtered and evaporated to dryness. This crude reaction product was then purified on a silica gel column using initially EtOAc/hexane (1:1) as eluent followed by MeOH/EtOAc (3:7) containing 2% Et3N to afford 2.9 gm of the title compound suitable for use in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[N:13]=2)=[N:6][CH:7]=1.C(N(C(C)C)C(C)C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[SH:86][CH2:87][CH2:88][C:89]([O:91][CH3:92])=[O:90]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O1CCOCC1>[CH3:92][O:91][C:89](=[O:90])[CH2:88][CH2:87][S:86][C:2]1[CH:3]=[C:4]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[N:13]=2)=[N:6][CH:7]=1
Reactant: COC(=O)CCS
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)CCSc1cnc(Nc2nc(CC3CCN(C(=O)OC(C)(C)C)CC3)cs2)c(Oc2ccccc2)c1
Temperature: 95 °C
Yield: 94.4 %

Procedure:
The atmosphere above a mixture of tert-butyl 4-((2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)piperidine-1-carboxylate (1.52 g, 2.79 mmol), N-ethyl-N-isopropylpropan-2-amine (0.971 mL, 5.57 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.161 g, 0.279 mmol), and dioxane (25 mL) was purged with nitrogen. Methyl 3-mercaptopropanoate (0.332 mL, 3.07 mmol) and Pd2dba3 (0.128 g, 0.139 mmol) were added, and the reaction was heated at 95° C. overnight. The reaction was cooled to ambient temperature and filtered through celite. The filtrate was concentrated and purified by MPLC (Biotage) eluting with 3:2 hexane:ethyl acetate to afford the title compound (1.54 g, 94.5% yield) as a tacky white solid: 1H NMR (CDCl3) δ 8.70 (s, 1H), 8.16 (s, 1H), 7.40 (t, 2H), 7.24 (t, 1H), 7.14 (s, 1H), 7.06 (d, 2H), 6.46 (s, 1H), 4.08 (m, 2H), 3.65 (s, 3H), 2.99 (t, 2H), 2.67 (m, 2H), 2.56 (d, 2H), 2.55 (t, 2H), 1.85 (m, 1H), 1.66 (m, 2H), 1.45 (s, 9H), 1.16 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:43]=[CH:42][C:38]2[N:39]=[CH:40][S:41][C:37]=2[CH:36]=1.CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:35]2[CH:43]=[CH:42][C:38]3[N:39]=[CH:40][S:41][C:37]=3[CH:36]=2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Reactant: Brc1ccc2ncsc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccc3ncsc3c2)c1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (74 mg, 0.16 mmol), 6-bromo-benzothiazole (34.9 mg, 0.16 mmol), and Pd[P(Ph)3]4 (12.1 mg, 6.4 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 5.6 mg. MS: 458.1 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 1.18-1.25 (m, 2H), 1.76-2.00 (m, 3H), 2.10-2.34 (m, 1H), 4.28-4.40 (m, 1H), 4.87-5.10 (m, 2H), 7.00-7.56 (m, 7H), 7.68-7.66 (m, 1H), 7.97-8.15 (m, 2H), 8.33-8.39 (m, 1H), 9.35-9.39 (s, 1H), 10.09-10.16 (s, 1H).