Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([O:8][CH3:9])[CH:7]=1.[C:11](OCC)(=[O:16])[CH2:12][C:13]([CH3:15])=O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:10][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[O:8][CH3:9])[NH:1][C:13]([CH3:15])=[CH:12][C:11]2=[O:16]
Reactant: COc1cc(N)ccc1Cl
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1cc2[nH]c(C)cc(=O)c2cc1Cl
Temperature: 90 °C
Yield: 45.3 %

Procedure:
A solution of 5-amino-2-chloroanisole (10.0 g, 63.5 mmol), ethyl acetoacetate (8.1 ml, 63.5 mmol) and catalytic para-toluene sulfonic acid (302 mg, 1.59 mmol) in 65 ml benzene over 4 A molecular sieves was stirred 6 hours at reflux (90° C. external temperature). The reaction mixture was then filtered and concentrated in vacuo. A mixture of the resulting residue and 6.4 ml DOWTHERM A was heated to 250° C. for 20 min. The reaction mixture was cooled to room temperature, and the precipitate was washed with hexanes and ethyl acetate to give 6.43 g (45% yield) of 6-chloro-7-methoxy-2-methylquinolin-4(1H)-one as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 11.54 (bs, 1H), 7.94 (s, 1H), 7.02 (s, 1H), 5.86 (s, 1H), 3.94 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([NH:25]C=O)[CH:6]=[C:7]([CH2:14][P:15]([O:21]C(C)C)([O:17]C(C)C)=[O:16])[CH2:8][CH2:9][O:10]C(=O)C)[CH3:2].C[Si](C)(C)Br.C(O)C>ClCCl>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([NH2:25])[CH:6]=[C:7]([CH2:14][P:15]([OH:17])([OH:21])=[O:16])[CH2:8][CH2:9][OH:10])[CH3:2]
Reactant: CCOC(=O)C(C=C(CCOC(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: C[Si](C)(C)Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(N)C=C(CCO)CP(=O)(O)O
Reaction time: 22 h

Procedure:
3.57 g (8.5 mmol) of 6-acetoxy-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester are dissolved in 22 ml of dichloromethane, and 4.4 ml (34 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 22 hours, 22 ml of ethanol are added dropwise, the mixture is left to stand for a further 22 hours and is concentrated by evaporation in a rotary evaporator, the residue is dissolved in 22 ml of ethanol, and a mixture of 22 ml of propylene oxide and 22 ml of ethanol is added dropwise. A suspension forms, which is stirred for a further 90 minutes and then filtered with suction. 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester having a melting point of 195° (decomp.) is obtained.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1B(O)O>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9]
Reactant: COc1ccc(Cl)c(B(O)O)c1
Reactant: Nc1ccc(Br)c(F)c1
Product: COc1ccc(Cl)c(-c2ccc(N)cc2F)c1
Yield: 92.7 %

Procedure:
The title compound (280 mg) was prepared from 4-bromo-3-fluoroaniline (227 mg, 1.2 mmol) and 2-chloro-5-methoxyphenylboronic acid (290 mg, 1.6 mmol) as a pale-yellow liquid.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Cl[C:48]1[C:53]([C:54]2[CH:59]=[CH:58][N:57]=[CH:56][N:55]=2)=[CH:52][CH:51]=[CH:50][N:49]=1.[C:60]([O:64][C:65](=[O:75])[NH:66][C:67]1[CH:72]=[CH:71][C:70]([CH3:73])=[C:69]([NH2:74])[CH:68]=1)([CH3:63])([CH3:62])[CH3:61].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:60]([O:64][C:65](=[O:75])[NH:66][C:67]1[CH:72]=[CH:71][C:70]([CH3:73])=[C:69]([NH:74][C:48]2[C:53]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][N:55]=3)=[CH:52][CH:51]=[CH:50][N:49]=2)[CH:68]=1)([CH3:63])([CH3:61])[CH3:62]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1N
Reactant: Clc1ncccc1-c1ccncn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1Nc1ncccc1-c1ccncn1
Temperature: 130 °C

Procedure:
The title compound was prepared according to the procedure described in Tetrahedron 2001, 51, 7027-7034. Pd(OAc)2 (47 mg, 0.21 mmol), and rac-BINAP (131 mg, 0.21 mmol) were stirred in toluene (12 mL) at RT for 12 minutes. This mixture was added to 4-(2-chloro-pyridin-3-yl)-pyrimidine (1.01 g, 5.24 mmol), (3-amino-4-methyl-phenyl)-carbamic acid tert-butyl ester (1.63 g, 7.34 mmol), and K2CO3 (14.5 g, 105 mmol) in toluene (40 mL). The mixture was heated overnight at 130° C. in a sealed tube. The cooled reaction was filtered through a pad of Celite, partially concentrated and the resulting solid was filtered to yield [4-methyl-3-(3-pyrimidin-4-yl-pyridin-2-ylamino)-phenyl]-carbamic acid tert-butyl ester.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12].O>CS(C)=O>[C:11]([NH:15][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)N
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)Nc1ccc([N+](=O)[O-])cc1
Yield: 72.5 %

Procedure:
A solution of 1-fluoro-4-nitro-benzene (1 g, 7.1 mmol) and tert-butylamine (1.5 g, 21 mmol) in DMSO (5 mL) was stirred at 75° C. overnight. The mixture was poured into water (10 mL) and extracted with EtOAc (7 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated under vacuum to dryness. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 30:1) to afford N-tert-butyl-4-nitroaniline (1 g, 73%). 1H NMR (CDCl3, 400 MHz) δ 8.03-8.00 (m, 2H), 6.61-6.57 (m, 2H), 4.67 (brs, 1H), 1.42 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[OH:10].[Cl-].[Al+3].[Cl-].[Cl-].[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17].Cl>[N+](C1C=CC=CC=1)([O-])=O>[OH:1][C:2]1[C:3]([OH:10])=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[C:7]=1[C:15]([CH:16]([CH3:18])[CH3:17])=[O:19]
Reactant: Oc1cc(O)c(O)c(O)c1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(C)C(=O)c1c(O)cc(O)c(O)c1O
Yield: 29.5 %

Procedure:
In a vessel fitted with a calcium chloride tube, 1.00 g (7.04 mmol) of 1,2,3,5-tetrahydroxybenzene (3) was dissolved in 20 ml of nitrobenzene and stirred. Into the stirred mixture, 2.82 g (21.1 mmol, 3.00 equivalents) of granular aluminum chloride was added piecemeal and stirred. One hour thereafter, a nitrobenzene (5.0 ml) solution of 0.750 g (7.04 mmol, 1.00 equivalent) of isobutyryl chloride was added dropwise. Ten hours thereafter, the reaction solution was poured into 100 ml of cold 2 M hydrochloric acid solution, stirred for 30 minutes, and then extracted from ether. The ether layer was washed with water, distilled to remove ether, combined with a large volume of water, and distilled water under reduced pressure to remove nitrobenzene by steam distillation. The residue was extracted from ether, washed with saturated brine, dried over sodium sulfate, and distilled under a reduced pressure to remove the solvent and obtain 1.38 g of crude product. By purifying the crude product by column chromatography (SiO2, 20 g of Wako Gel C-300, hexane:ether=1:1), 441 mg (yield 65.9%) of the product (8) was obtained in the form of yellow powder crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][CH2:18][CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33]([NH:35][C@H:36]([CH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)[CH2:37][CH2:38][C:39](O)=[O:40])=[O:34])([CH3:31])([CH3:30])[CH3:29].C1C=CC2N(O)N=NC=2C=1.CNC(N=C=NCC)CCNC>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:12][CH2:13][C@@H:14]([N:17]([CH2:18][CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:39](=[O:40])[CH2:38][CH2:37][C@H:36]([NH:35][C:33]([O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:34])[CH:42]2[CH2:43][CH2:44][O:45][CH2:46][CH2:47]2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C1CCOCC1
Reactant: O=C(OCc1ccccc1)[C@H]1CC[C@@H](NCCOCc2ccccc2)CC1
Agent: CCN=C=NC(CCNC)NC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)N(CCOCc1ccccc1)[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cooled solution of cis-4-(2-benzyloxy-ethylamino)-cyclohexanecarboxylic acid benzyl ester (3 g, 8.2 mmol), 4-tert-butoxycarbonylamino-4-(S)-tetrahydro-pyran-4-yl-butyric acid (2.4 g, 8.4 mmol) (prepared as in Example 35) and HOBT (2.4 g, 10.5 mmol) in CH2Cl2 (100 mL) was added TEA (2.3 mL), followed by addition of 1,3-dimethylamino propyl-3-ethylcarbodiimide (EDC, 2.0 g, 10 mmol). The reaction mixture was allowed to warm to room temperature and then was stirred overnight. EtOAc (200 mL) was added and the resulting mixture washed with citric acid solution, NaHCO3 solution, and aq. NaCl solution. The organic layer was dried with MgSO4. The EtOAc was evaporated to yield a colorless oil. The colorless oil (crude product) was purified by column chromatography (1:1 EtOAc/Hexane) to yield 4-{(2-benzyloxy-ethyl)-[4-tert-butoxycarbonylamino-4-(S)-(tetrahydro-pyran-4-yl)-butyryl]-amino}-cis-cyclohexanecarboxylic acid benzyl ester as a residue.
Reaction SMILES: [C:1]1([C@@:7]23[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C@@H:8]2[CH2:9][NH:10][CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][C:28]#[N:29]>CN(C)C=O>[C:28]([CH2:27][N:10]1[CH2:11][CH2:12][C@:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C@@H:8]2[CH2:9]1)#[N:29]
Reactant: N#CCCl
Reactant: c1ccc([C@]23CCNC[C@H]2c2ccccc2O3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCN1CC[C@]2(c3ccccc3)Oc3ccccc3[C@@H]2C1
Yield: 99.7 %

Procedure:
To a solution of 3.02 g of cis-1,2,3,4,4a,9b-hexahydro-4a-phenyl-benzofuro[3,2-c]pyridine in 48 ml of dry dimethylformamide was added 3.6 g of anhydrous potassium carbonate and 0.982 g of chloroacetonitrile. The resulting suspension was heated at 80° under nitrogen for 19 hours. The cooled reaction mixture was dried with 500 ml of ether and washed with water (4×250 ml). The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to give 3.48 g (99.9%) of a gum, which crystallized on standing. A 0.35 g portion of this material was recrystallized from ethanol to afford 0.22 g of crystals, m.p. s 93, 94°-96°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH:16]3[CH3:20])[N:12]=[C:11]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30](Br)=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:34]([Cu])#[N:35]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH:16]3[CH3:20])[N:12]=[C:11]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([C:34]#[N:35])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC1CCCN1c1nc(-c2ccc(F)c(Cl)c2)cc(N2CCN(c3ncc(Br)cn3)CC2)n1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1CCCN1c1nc(-c2ccc(F)c(Cl)c2)cc(N2CCN(c3ncc(C#N)cn3)CC2)n1

Procedure:
Heat a mixture of 2-{4-[6-(3-chloro-4-fluorophenyl)-2-(2-methylpyrrolidin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-5-bromopyrimidine (478 mg) and CuCN (270 mg) in DMF at 150° C. for 16 h in a round bottom flask that is open to the air. Let cool, dilute with EtOAc (15 mL), wash with water (3×10 mL), dry (Na2SO4), and evaporate. Purify by silica gel chromatography, eluting with 3:1 hexanes:EtOAc to provide the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:20][CH2:19]1.CCCCCC>O>[OH:16][C:8]1[CH:7]=[CH:6][C:5]([C@@H:3]([OH:4])[CH2:2][NH:1][CH:36]2[CH2:35][CH2:34][N:33]([C:30]3[CH:29]=[CH:28][C:27]([S:24]([N:21]4[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]4)(=[O:26])=[O:25])=[CH:32][CH:31]=3)[CH2:38][CH2:37]2)=[CH:10][C:9]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: CN1CCN(S(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Solvent: CCCCCC
Solvent: O
Product: CN1CCN(S(=O)(=O)c2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)CC1

Procedure:
The title compound was prepared from N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide, and 1-{4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl}-4-piperidinone in substantially the same manner, as described in Example 50. The product was obtained as a brown solid; mp: 89-91° C.; 1H NMR (400 MHz, DMSO-d6): δ 1.53-1.65 (m, 2H), 2.06-2.16 (m, 2H), 2.82-2.89 (m, 2H), 2.94 (s, 3H), 3.09-3.13 (m, 2H), 3.70 (brs, 2H), 4.01-4.05 (m, 2H), 4.76-4.79 (d, 2H), 6.11 (brs, 1H), 6.88-6.90 (d, 2H), 7.06-7.13 (m, 4H), 7.25 (s, 1H), 7.52-7.55 (d, 2H), 8.60 (brs, 1H); 8.58 (brs, 1H); 8.75 (s, 1H), 9.64 (brs, 1H), 10.00 (s, 1H); MS m/z 568 (M+H)+; Analysis for C25H37N5O6S2×0.4 hexane×0.52 H2O Calc'd: C, 42.07; H, 4.93; N, 7.34; Found: C, 42.27; H, 4.60; N, 6.70.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[N:11]=[C:10]([CH3:12])[C:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:7]2[CH:30]=1)(=O)[NH2:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1.O>C1COCC1>[C:1]([C:4]1[N:5]=[C:6]2[N:11]=[C:10]([CH3:12])[C:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:7]2[CH:30]=1)(=[S:40])[NH2:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1nc2nc(C(N)=O)cn2c(-c2ccc(Cl)cc2Cl)c1CNC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2nc(C(N)=S)cn2c(-c2ccc(Cl)cc2Cl)c1CNC(=O)OC(C)(C)C
Temperature: 65 °C
Yield: 220.3 %

Procedure:
To a stirred solution of tert-butyl (2-carbamoyl-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-6-yl)methylcarbamate (intermediate for Example 62, 150 mg, 0.33 mmol) in THF (10 mL) was added Lawesson's reagent (202 mg, 0.50 mmol). After heating to 65° C. for 20 h, the reaction mixture was poured into H2O (5 mL). The resulting mixture was extracted with EtOAc and the organic layer was washed with satd aq NH4Cl and brine prior to drying over MgSO4. Filtration, concentration under reduced pressure afforded crude tert-butyl (2-carbamothioyl-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-6-yl)methylcarbamate (339 mg, 100% crude yield) as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:20]=[CH:19][C:13](/[CH:14]=[CH:15]/B(O)O)=[CH:12][CH:11]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:6]1[CH:7]=[C:2](/[CH:15]=[CH:14]/[C:13]2[CH:19]=[CH:20][C:10]([Cl:9])=[CH:11][CH:12]=2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(/C=C/c2cc(Cl)ncn2)cc1
Temperature: 40 °C
Reaction time: 48 h
Yield: 24.4 %

Procedure:
A mixture of commercially available 4,6-dichloropyrimidine (300 mg, 2.01 mmol), (E)-4-chlorostyrylboronic acid (441 mg, 2.41 mmol), potassium phosphate (1282 mg, 6.04 mmol), and PalladiumTetrakis (116 mg, 0.10 mmol) in DMF (1 mL) was stirred under nitrogen at 40° C. for 2 days. The reaction was filtered, diluted with CH2Cl2, washed with water, brine, dried (MgSO4), and concentrated. The crude product was purified using ISCO flash chromatography (silica gel/hexanes/ethyl acetate 100:0 to 50:50 gradient) to afford the desired product (E)-4-chloro-6-(4-chlorostyryl)pyrimidine 20A (120 mg, 0.49 mmol, 23.73% yield) as a light yellow solid. LC/MS 252 (M+H)+, tR 1.07 min (method 5).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[C:11]([O:16][CH3:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[C:19]([O:23][C:24](=[O:27])[CH2:25][Zn+])([CH3:22])([CH3:21])[CH3:20].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1COCC1.C(OCC)(=O)C.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]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:25][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:27])=[C:11]([O:16][CH3:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: COc1cc(OCc2ccccc2)ccc1Br
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(OCc2ccccc2)ccc1CC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 98.2 %

Procedure:
To a solution of 4-(benzyloxy)-1-bromo-2-methoxybenzene (2.0 g, 6.82 mmol) in THF (20 ml) was added 2-tert-butoxy-2-oxoethylzinc chloride (27.3 ml, 13.64 mmol). Nitrogen gas bubbled through the mixture for 10 min. then Pd2(dba)3 (0.312 g, 0.341 mmol) and X-PHOS (0.325 g, 0.682 mmol) were added and the resulting mixture heated at 60° C. for 30 min. The mixture was cooled, diluted with ethyl acetate (20 mL), washed with aqueous ammonium chloride (saturated, 1×15 mL), dried over MgSO4, filtered and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 50M, using a gradient eluant of EtOAc/Hexane (0-50%) to afford the title compound (2.2 g, 98%). LC/MS (m/z): 351 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17]#[N:18].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:16][C:17]#[N:18]
Reactant: Sc1ccccc1Br
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCSc1ccccc1Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.4 %

Procedure:
A mixture of 2-bromobenzenethiol (6.3 mL, 53 mmol), K2CO3 (13.8 g, 100 mmol) and 2-chloroacetonitrile (3.2 mL, 50 mmol) in DMF (50 mL) was stirred at 25° C. for 6 h, poured into water (700 mL), and extracted with petroleum ether (300 mL) followed by DCM (2×200 mL). The combined DCM extracts were concentrated to dryness, and re-dissolved in petroleum ether/ethyl acetate (10:1, 600 mL). The organic solution was washed with water (250 mL) and brine (250 mL), dried over Na2SO4, filtered and concentrated to dryness to give the title compound (11 g, 85%). 1H NMR (300 MHz, CDCl3) δ 7.67 (dd, J=7.8, 1.5, 1H), 7.60 (dd, J=7.8, 1.5, 1H), 7.41 (m, 1H), 7.25 (m, 1H), 3.68 (s, 2H).
Reaction SMILES: [C:1](NCC(O)=O)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].C(N(CC)C(C)C)(C)C.[NH2:32][CH2:33][C:34]([NH:36][C:37]1[CH:51]=[CH:50][C:40]([CH2:41][NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:39][CH:38]=1)=[O:35]>CN(C=O)C>[C:45]([O:44][C:43]([NH:42][CH2:41][C:40]1[CH:39]=[CH:38][C:37]([NH:36][C:34](=[O:35])[CH2:33][NH:32][C:1](=[O:2])[O:3][CH2:4][CH:5]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:51][CH:50]=1)=[O:49])([CH3:46])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CN)cc1
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of Fmoc-Glycine (16 g, 54 mmol, 1.0 eq.) in dry DMF (160 mL) at 0° C. was added N,N-diisopropylethylamine (14 g, 108 mmol, 2.0 eq) and N N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (16 g, 54 mmol, 1.0 eq). The mixture was stirred at 0° C. for 30 min and a solution of tert-butyl [4-(glycylamino)benzyl]carbamate (12 g, 54 mmol, 1.0 eq.) in dry DMF (50 mL) was added. The mixture was stirred at room temperature overnight poured into ice water (400 mL) and extracted with EtOAc (400 mL×2). The organic layer was washed with brine (200 mL×2), dried over Na2SO4 and concentrated in vacuum. The residue was re-crystallized from EtOAc (200 mL) and petroleum ether (400 mL) to afford #B118 (18 g, 66.6%) as a white solid. 1H NMR (400 Hz, DMSO-d6): δ 9.93 (s, 1H), 7.91 (d, 2H), 7.75 (d, 2H), 7.61 (m, 1H), 7.52 (d, 2H), 7.43 (m, 2H), 7.36 (m, 3H), 7.18 (d, 3H), 4.32 (d, 2H), 4.26 (m, 1H), 4.07 (d, 2H), 3.80 (d, 2H), 1.39 (s, 9H)
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:17])[CH2:13][C:14]([OH:16])=O)[CH2:8][CH2:7]1)=[O:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:43]1([N:49]2[CH:53]=[C:52]([NH2:54])[CH:51]=[N:50]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:17])[CH2:13][C:14]([NH:54][C:52]2[CH:51]=[N:50][N:49]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:53]=2)=[O:16])[CH2:10][CH2:11]1)=[O:5]
Reactant: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1
Reactant: Nc1cnn(-c2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1)Nc1cnn(-c2ccccc2)c1
Reaction time: 0.03 h
Yield: 36 %

Procedure:
DMAP (68 mg, 0.56 mmol) was added to 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-propionic acid (100 mg, 0.28 mmol) in DMF (2 mL) followed by EDCI (64 mg, 0.33 mmol) and HOBT (45 mg, 0.33 mmol). After 2 minutes, 1-phenyl-1H-pyrazol-4-ylamine (54 mg, 0.33 mmol) was added and stirring was continued at room temperature overnight. Cold water was then added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford 50 mg (35.97% yield) of 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-N-(1-phenyl-1H-pyrazol-4-yl)-propionamide. LC/MS [M+H]+: 596.09, 87.79%. 1H NMR (300 MHz, DMSO-d6): δ 10.4 (d, 1H), 8.5 (d, 1H), 7.84-7.64 (m, 4H), 7.54-7.2 (m, 5H), 4.0-3.8 (m, 7H), 3.2-3.1 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([CH:16]=[CH2:17])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.Br[CH:19]([C:24]1[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=1)[C:20]([F:23])([F:22])[F:21].N1C=CC=CC=1C1C=CC=CN=1>ClC1C=CC=CC=1Cl.Cl[Cu]>[Cl:1][C:2]1[CH:15]=[C:14](/[CH:16]=[CH:17]/[CH:19]([C:24]2[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=2)[C:20]([F:22])([F:21])[F:23])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: FC(F)(F)C(Br)c1cc(Cl)c(Cl)c(Cl)c1
Reactant: C=Cc1ccc(CNc2ccccn2)c(Cl)c1
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: FC(F)(F)C(/C=C/c1ccc(CNc2ccccn2)c(Cl)c1)c1cc(Cl)c(Cl)c(Cl)c1
Temperature: 180 °C
Reaction time: 24 h
Yield: 32.4 %

Procedure:
To a stirred solution of N-(2-chloro-4-vinylbenzyl)pyridin-2-amine (0.3 g, 1.22 mmol) in 1,2-dichlorobenzene (5 mL) were added 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (0.83 g, 2.44 mmol), CuCl (24 mg, 0.24 mmol) and 2,2-bipyridyl (76 mg, 0.48 mmol). The resultant reaction mixture was degassed with argon for 30 min and then stirred at 180° C. for 24 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 15% EtOAc in n-hexane) afforded the title compound as an off-white solid (0.2 g, 35%): mp 140-142° C.; 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=4.0 Hz, 1H), 7.40 (m, 5H), 7.22 (m, 1H), 6.61 (m, 2H), 6.35 (m, 2H), 4.94 (br s, 1H), 4.61 (d, J=6.4 Hz, 2H), 4.11 (m, 1H); ESIMS m/z 505.39 ([M+H]+).