Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[C:11](N3CCCCC3)[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]2=3)[CH2:4][CH2:3]1.C[OH:30]>O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][C:11](=[O:30])[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]2=3)[CH2:4][CH2:3]1
Reactant: CO
Reactant: CN1CCC(=C2c3ccccc3C=C(N3CCCCC3)c3ccccc32)CC1
Solvent: O
Product: CN1CCC(=C2c3ccccc3CC(=O)c3ccccc32)CC1

Procedure:
This enamine product is then hydrolyzed by refluxing with stirring in 150 ml. 10% in water and 75 ml. of methanol. The methanol is then removed by evaporation of the reaction mixture on a rotary evaporator. The residual material containing the desired product is made alkaline by adding solid NaHCO3 until no more CO2 is evolved. The residue is then extracted with toluene and ether. The combined extracts containing the product are dried over anhydrous MgSO4, filtered, and the solvents removed with a rotary evaporator. There remains a dark brown residual oil which when seeded crystallizes slowly. This product is collected and recrystallized from hexane two times to give 1-methyl-4-(10,11-dihydro-10-oxo-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, m.p. 138°-140°C. Three more recrystallizations from hexane gives product, m.p. 141°-142°C.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(Cl)cc1
Yield: 29.3 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 63 mg, 0.2 mmol) was reacted with 4-chlorophenylboronic acid (available from Combi-Blocks Inc.; 56 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (27 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.37 (s, 1H), 8.33 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.51 (d, J=6.8 Hz, 2H), 7.42 (d, J=6.8 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:14]([SH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CS(C)=O>[CH2:14]([S:21][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1cnccn1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: c1ccc(CSc2cnccn2)cc1
Yield: 45.6 %

Procedure:
In a similar fashion using route 38 general procedure 92, 2-chloropyrazine (1 g, 8.73 mmol), K2CO3 (1.80 g 13.1 mmol), benzylmercaptan (1.62 g 13.1 mmol) and DMSO (8 ml) at 150° C. for 4 h in sealed tube gave the title compound (805 mg, 45%) after purification by column chromatography with n-hexane/EtOAc (97:3) as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]([OH:17])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C1C=CC=CC=1.C(N(CC)C#CC)C.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][C:43]=1[O:44][CH3:45])[C:40](=[CH:46][C:47]1[CH:52]=[C:51]([O:53][CH3:54])[C:50]([O:55][CH3:56])=[C:49]([O:57][CH3:58])[CH:48]=1)[NH:39][CH2:38][CH2:37]2>N1C=CC=CC=1>[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][C:43]=1[O:44][CH3:45])/[C:40](=[CH:46]/[C:47]1[CH:52]=[C:51]([O:53][CH3:54])[C:50]([O:55][CH3:56])=[C:49]([O:57][CH3:58])[CH:48]=1)/[N:39]([C:15](=[O:17])/[CH:14]=[CH:13]/[C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:38][CH2:37]2
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1OC
Reactant: COc1cc2c(cc1OC)C(=Cc1cc(OC)c(OC)c(OC)c1)NCC2
Agent: CC#CN(CC)CC
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)/C(=C/c1cc(OC)c(OC)c(OC)c1)N(C(=O)/C=C/c1cc(OC)c(OC)c(OC)c1)CC2

Procedure:
To a solution of 100 parts of 3-(3,4,5-trimethoxyphenyl)-2-propenoic acid in 1125 parts of benzene is added 22 parts of N,N-diethyl-1-propyne-1-amine. The resultant mixture is stirred for 2 hours, whereupon a solution of 75 parts of 3,4-dihydro-6,7-dimethoxy-1-[(3,4,5-trimethoxyphenyl)methylene]isoquinoline [Ber. deut. chem. Ges., 55, 2889 (1922)] in 200 parts of pyridine is introduced. The mixture thus obtained is stirred and heated at 65° for 3 hours, then cooled, consecutively washed with water and aqueous 5% sodium bicarbonate, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residue is crystallized from a mixture of ethyl acetate and ether to give (1Z,2E)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-[(3,4,5-trimethoxyphenyl)methylene]-2-[3-(3,4,5-trimethoxyphenyl)-1-oxo-2-propenyl]isoquinoline melting at 180°-183°.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:6][O:5][C:4]([C:7]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([O:16]C)[C:9]=3[CH:8]=2)=[N:3]1.B(Br)(Br)Br>>[CH3:1][C:2]1([CH3:18])[CH2:6][O:5][C:4]([C:7]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([OH:16])[C:9]=3[CH:8]=2)=[N:3]1
Reactant: COc1cccc2oc(C3=NC(C)(C)CO3)cc12
Agent: BrB(Br)Br
Product: CC1(C)COC(c2cc3c(O)cccc3o2)=N1
Yield: 87.3 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 5 using 2-(4,4-dimethyloxazolin-2-yl)-4-methoxybenzo(b)furan (6.11 g) and boron tribromide (6.11 ml), the title compound (5.03 g) was obtained as pale-yellow crystals, melting point 187-188° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:56])/[C:18](/[C:31]3[N:32]=[C:33]([NH:36]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:34][CH:35]=3)=[N:19]\[O:20][C:21]([C:24]([O:26]C(C)(C)C)=[O:25])([CH3:23])[CH3:22])[C:14](=[O:57])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])=[N+]=[N-].C(O)(C(F)(F)F)=O>[Ni].O>[NH2:1][CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:56])/[C:18](/[C:31]3[N:32]=[C:33]([NH2:36])[S:34][CH:35]=3)=[N:19]\[O:20][C:21]([C:24]([OH:26])=[O:25])([CH3:23])[CH3:22])[C:14](=[O:57])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Ni]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN)CS[C@H]12)c1csc(N)n1)C(=O)O
Reaction time: 1 h
Yield: 35.1 %

Procedure:
An aqueous slurry of Raney nickel (10.2 g.) was added in one portion to a stirred solution of the azide (20.0 g.) in a mixture of MEOH (60 ml.) and TFA (60 ml.) at room temperature. A vigorous effervescence was observed. Stirring was continued for 1 hour and the Raney nickel was removed by filtration through diatomaceous earth. The filter pad was washed well with MEOH and the washings were combined with the filtrate. The solvents were evaporated under reduced pressure to give a pale green solid residue which was then stirred for 2 hours with a mixture of TFA (60 ml.) and water (15 ml.). This mixture was evaporated to dryness and the residue was stirred vigorously with water (400 ml.) for 30 minutes. The resulting solution was filtered through diatomaceous earth to remove the undissolved triphenylmethanol and the filtrate was applied to a column of Diaion HP 20 resin (1 l.). The column was eluted with water (500 ml.) to remove inorganic material and then with aqueous MEOH 1:1 v/v. The fractions which were shown by HPLC to contain the product were evaporated under reduced pressure to yield 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid (4.2 g.) as a pale yellow foam having the following n.m.r. in solvent A: 1.4 (s,6H); 3.1-3.8 (complex, 4H); 4.95 (d,1H); 5.7(d,1H); 6.72 (s,1H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][OH:6])=[N+:2]=[N-:3].[C:7]([Si:11](Cl)([CH3:13])[CH3:12])([CH3:10])([CH3:9])[CH3:8]>>[N:1]([CH2:4][CH2:5][O:6][Si:11]([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:13])[CH3:12])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC(C)(C)[Si](C)(C)OCCN=[N+]=[N-]

Procedure:
protecting the hydroxy group of 2-azidoethanol with tert-butylchloro-dimethylsilane to produce 1-azido-2-(tertbutyl-dimethylsiloxy)ethane;
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([OH:16])=O)([O-])=O.CC(O)=O>[Pd].CO>[NH2:10][C:8]1[CH:9]=[C:4]2[C:5]([CH2:13][C:14](=[O:16])[NH:1]2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc2c(c1)NC(=O)C2
Reaction time: 8 h
Yield: 70.5 %

Procedure:
A solution of 2-(2,4-dinitrophenyl)acetic acid (1.0 g, 4.42 mmol), AcOH (10 mL), and MeOH (5 mL) was purged with Ar for 15 minutes at which time 10 wt. % Pd/C (100 mg) was added. The mixture was then purged briefly with H2 and then stirred under 1 atm of H2 overnight. The mixture was filtered through a pad of celite, the solvent removed in vacuo, and the residue purified by column chromatography (silica gel, 90:10 CH2Cl2/MeOH) to give 462 mg, 71% of a brown solid. 1H NMR (400 MHz, CD3OD) δ 6.95 (d, J=7.7 Hz, 1H), 6.37 (d, J=7.8 Hz, 1H), 6.34 (s, 1H), 3.38 (s, 2H); MS ESI 149.0 [M+H]+, calcd for [C8H8N2O+H]+149.07.
Reaction SMILES: [CH:1]([P:3](=[O:14])([O-:13])[O:4][CH2:5][CH:6]([CH2:11][CH3:12])[CH2:7][CH2:8][CH2:9][CH3:10])=[CH2:2].[CH2:15]([NH2:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[H-].[Na+].O>C(OCC)(=O)C>[CH2:11]([CH:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:5][O:4][P:3]([CH2:1][CH2:2][NH:33][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:13])[O:14][CH2:5][CH:6]([CH2:11][CH3:12])[CH2:7][CH2:8][CH2:9][CH3:10])[CH3:12]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: C=CP(=O)([O-])OCC(CC)CCCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCNCCP(=O)(OCC(CC)CCCC)OCC(CC)CCCC
Temperature: 140 °C
Reaction time: 6 h

Procedure:
A mixture of 2-ethylhexyl vinylphosphonate (49.90 g), octadecylamine (40.43 g) and sodium hydride 0.10 g was stirred at 140° C. for 6 hours. Water (100 ml) and ethyl acetate (200 ml) were added. The organic phase was separated, dried with sodium sulfate, filtered and the solvent evaporated under reduced pressure to give di(2-ethylhexyl)[2-(octadecylamino)ethyl]phosphonate, as colourless liquid nD40 =1.4541.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C@@H:9]([C:17]([OH:19])=O)[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=1)[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:7]([CH2:8][C@H:9]([NH:10][C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])[C:17]2=[O:19])=[CH:20][CH:21]=1)[CH3:2]
Reactant: CCOc1ccc(C[C@H](NC(=O)C(F)(F)F)C(=O)O)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc2c(c1)C(=O)[C@@H](NC(=O)C(F)(F)F)C2
Reaction time: 1 h

Procedure:
O-Ethyl-N-trifluoroacetyl-L-tyrosine (XIII, Example 17, 1.52 g, 5 mmol) and ferric chloride (0.89 g, 5 mmol) are suspended in methylene chloride (36 mL). Trifluoroacetic anhydride (2.12 mL, 15 mmol) is added over 1 hr at 20-25°. The reaction is stirred for 1 hr and then quenched with water (36 mL). The organic layer is separated and mixed with methanol (7 mL). The mixture is cooled to −20° for 1 hr and then filtered to give the same title compound as EXAMPLE 4.
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([C:13]([OH:15])=O)[CH:8]=1.C(Cl)(C([Cl:20])=O)=O>C(Cl)Cl>[Cl:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([C:13]([Cl:20])=[O:15])[CH:8]=1
Reactant: O=C(O)c1cc(Cl)ncn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
A drop of DMF was added to a stirred solution of 6-chloropyrimidine-4-carboxylic acid (5.5 g, 34.7 mmol) and (COCl)2 (12 mL) in DCM (100 mL). The mixture was stirred at 25° C. for 2 h. The solvent was evaporated under reduced pressure to give crude 6-chloropyrimidine-4-carbonyl chloride (6.0 g, yield: 97.7%). 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.10 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][C@H:4]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.[NH2:25][CH:26]([CH2:38][CH2:39][CH3:40])[C@@H:27]([C:29]1[O:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1)[OH:28]>>[O:30]1[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=[C:29]1[C:27]([C@@H:26]([NH:25][C:5](=[O:7])[CH:4]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[CH2:3][C:2]([CH3:1])([CH3:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:38][CH2:39][CH3:40])=[O:28]
Reactant: CC(C)(Cc1ccccc1)C[C@H](CC(=O)N1CCOCC1)C(=O)O
Reactant: CCCC(N)[C@H](O)c1nc2ccccc2o1
Product: CCC[C@H](NC(=O)C(CC(=O)N1CCOCC1)CC(C)(C)Cc1ccccc1)C(=O)c1nc2ccccc2o1

Procedure:
It is similarly prepared according to general procedure given for example 10 above but using (R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid and (S)-2-Amino-1-benzoxazol-2-yl-pentan-1-ol.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:21]=[N:20][C:19]4[C:14]3=[N:15][CH:16]=[N:17][C:18]=4[C:22]3[CH:27]=[CH:26][C:25]([CH2:28]O)=[CH:24][CH:23]=3)[CH:7]=2)[CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:32][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:18]2[N:17]=[CH:16][N:15]=[C:14]3[C:19]=2[N:20]=[CH:21][N:13]3[C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=2[CH3:12])[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:30])=[CH:23][CH:24]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(-c3ccc(CO)cc3)ncnc21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(-c3ccc(CBr)cc3)ncnc21
Temperature: 25 °C

Procedure:
To a mixture of N-cyclopropyl-3-[6-(4-hydroxymethyl-phenyl)-purin-9-yl]-4-methyl-benzamide (58 mg, 0.145 mmol, see example 4C-3 1) in dichloromethane (0.5 ml) was added carbon tetrabromide (58 mg, 0.175 mmol) then triphenylphosphine (47 mg, 0.179 mmol). The mixture was stirred at RT for an hour, then purified by a column eluting with EtOAc/Hex. (1:1) to give the desired product as a crude (88 mg, 0.19 mmol, 63%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:13]([CH2:21][CH3:22])[CH2:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:56][C@H:57]1[CH2:61][NH:60][C@H:59]([C:62]([O:64][CH3:65])=[O:63])[CH2:58]1>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([CH2:21][CH3:22])[CH2:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([N:60]1[CH2:61][C@H:57]([OH:56])[CH2:58][C@H:59]1[C:62]([O:64][CH3:65])=[O:63])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCCC(C)C[C@@H](CC)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(C)C[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3R)-2-(tert-butoxycarbonylamino)-3-ethyl-5-methylnon-8-enoic acid (2 g, 6.38 mmole) in dichloromethane (20 mL) was added DIPEA (1.93 mL, 19.19 mmole), HATU (2.42 g, 6.38 mmole) followed by (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate (1.15 g, 6.38 mmole) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mass was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude compound. The crude compound was taken to the next step without further purification (1.5 g, 53.4%). MS: MS m/z 441.6 (M++1)
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19]C)=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br.C(=O)([O-])[O-].[K+].[K+].[OH-].[Li+]>CN(C)C=O.O1CCCC1.O>[CH3:1][C:2]1[N:3]([CH2:21][C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[CH3:24])[C:4]2[CH:10]=[C:9]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:5]=2[N:6]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C)[nH]c12
Reactant: Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccccc1Cn1c(C)nc2c(C(=O)O)cc(N3CCOCC3)cc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 57.5 %

Procedure:
To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 26, step d (0.2 g, 0.726 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 2-methylbenzyl bromide (0.145 mL, 1.090 mmol) and potassium carbonate (0.301 g, 2.179 mmol). The resulting reaction mixture was stirred for 3 h at 80° C. The solution was cooled to room temperature and poured into water and was extracted with EtOAc. The combined organic phase was washed with Brine and concentrated. The residue was purified on a Biotage Isolera purification system using a Biotage 10 g SNAP silica gel cartridge and eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes. The expected compound was collected and evaporated to yield a tan solid. The tan solid was dissolved in tetrahydrofuran (THF) (10.00 mL) followed by the addition of 1M lithium hydroxide solution (10 mL, 10 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature and the organic solvent was removed in-vacuo. The solution was diluted with water (20 mL) and acidified with 1 N HCl. The mixture was then filtered and the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v)(10-40%) over 10 minutes. The appropriate fractions were collected and evaporated to yield the desired product (152.6 mg, 0.418 mmol, 57.5% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.45 (s, 3H) 2.87 (s, 3H) 3.00 (br. s., 4H) 3.72-3.81 (m, 4H) 5.53 (s, 2H) 6.60 (d, J=7.58 Hz, 1H) 6.78 (d, J=1.26 Hz, 1H) 7.14 (t, 1H) 7.23-7.33 (m, 3H). MS (ES+) m/e 365.8 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>C(#N)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>[OH:29][CH2:25][CH2:26][C:27]#[C:28][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccn2cc(-c3ccc(Br)cc3)nc2c1
Reactant: C#CCCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccn2cc(-c3ccc(C#CCCO)cc3)nc2c1
Temperature: 60 °C
Yield: 71.7 %

Procedure:
The product of Step A (1.8 g) in dry acetonitrile (40 mL) was treated sequentially with tetrakis(triphenylphosphine)palladium(0) (0.1 g), triethylamine (1.27 g), and Cul (10 mg) then heated at 60° C. for 30 minutes. The mixture was cooled to ambient temperature, treated with 3-butyn-1-ol (0.361 g) and heated at reflux temperature for 18 hours. The mixture was cooled to ambient temperature and evaporated to dryness. The residue was crystallized, twice, from acetone to afford the title compound (1.02 g).
Reaction SMILES: [BH4-].[Na+].[CH3:3][NH2:4].[F:5][C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=1)[CH2:9][NH:10][C:11]([NH:13][C:14]1[S:15][C:16]([CH:21]([CH3:23])[CH3:22])=[C:17]([CH:19]=O)[N:18]=1)=[O:12]>>[F:5][C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=1)[CH2:9][NH:10][C:11]([NH:13][C:14]1[S:15][C:16]([CH:21]([CH3:23])[CH3:22])=[C:17]([CH2:19][NH:4][CH3:3])[N:18]=1)=[O:12]
Reactant: CC(C)c1sc(NC(=O)NCc2cccc(F)c2)nc1C=O
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Product: CNCc1nc(NC(=O)NCc2cccc(F)c2)sc1C(C)C
Reaction time: 6 h

Procedure:
NaBH4 (100 mg, 3 mmol) was added in portions to a mixture of MeNH2 (5 mL, 30% in EtOH) and 1-(3-fluorobenzyl)-3-(4-formyl-5-isopropylthiazol-2-yl)urea (322 mg, 1 mmol) at 0 C. The mixture was stirred for 6 hours then quenched with dilute HCl solution. Basic aqueous work-up with CH2Cl2 followed by flash chromatography afforded 1-(3-fluorobenzyl)-3-(5-isopropyl-4-((methylamino)methyl)thiazol-2-yl)urea. MS (ES+): M/Z 337 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]1=[O:4].[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([Cl:18])=[CH:13][N:12]=1.C([O-])(O)=O.[Na+]>CO.O>[Cl:10][C:11]1[N:16]=[C:15]([NH:1][CH:2]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]2=[O:4])[C:14]([Cl:18])=[CH:13][N:12]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: NC1CCCCNC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1NCCCCC1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of (±)-α-amino-ε-caprolactam (256 mg, 2.0 mmol), 2,4,5-trichloropyrimidine (366 mg, 2.0 mmol, 1 equiv.) and NaHCO3 (168 mg, 2 mmol, 1 equiv.) in a mixture of MeOH (12 mL) and H2O (6 mL) was stirred at room temperature for 15 h. The resulting precipitate was collected by vacuum filtration and washed with small amounts of MeOH and water, providing the product 3-(2,5-dichloropyrimidin-4-ylamino)azepan-2-one; ESMS m/z 275.0 (M+H+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].C(N(CC)CC)C.[CH3:14][Si:15]([CH3:18])([CH3:17])Cl>C1C=CC=CC=1>[CH3:1][N:2]([Si:15]([CH3:18])([CH3:17])[CH3:14])[CH2:3][CH2:4][N:5]([CH3:6])[Si:15]([CH3:18])([CH3:17])[CH3:14]
Reactant: C[Si](C)(C)Cl
Reactant: CNCCNC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(CCN(C)[Si](C)(C)C)[Si](C)(C)C
Reaction time: 3.5 h

Procedure:
A mixture of 176 parts by weight of N,N'-dimethylethylenediamine, 1000 parts by volume of benzene and 552 parts by volume of triethylamine were stirred at room temperature and at the same time 434 parts by weight of trimethylchlorosilane, diluted with 500 parts by volume of benzene, were added dropwise over the course of 3 hours. The mixture was stirred for a further 3.5 hours and left to stand overnight, and the precipitate present was filtered off and washed with benzene. The combined filtrates were concentrated in a rotary evaporator and the residue was distilled in vacuo.
Reaction SMILES: [F:1][CH:2]([F:9])[CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][NH:4]1.Br[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[F:1][CH:2]([F:9])[CH:3]1[CH2:8][N:7]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH2:6][CH2:5][N:4]1[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: FC(F)C1CNCCN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CCN2CCN(CCc3ccc([N+](=O)[O-])cc3)C(C(F)F)C2)cc1
Temperature: 80 °C

Procedure:
A mixture of 2-Difluoromethyl Piperazine (80 mg, 0.41 mmol), 1-(2-bromoethyl)-4-nitrobenzene (373 mg, 1.6 mmol), tetrabutylammonium iodide (15 mg, 0.16 mmol), and K2CO3 (220 mg, 1.6 mmol) in DMF (2 mL) was heated to 80° C. for 2 days. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 435 [M+1]+. (0.44 μM)