Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[C:11]([F:17])[CH:10]=1>C1C(Cl)=CC=C(Cl)C=1.O>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:11]([F:17])[CH:10]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Clc1ccc(Cl)cc1
Product: COCCOCc1ccc(Br)cc1F
Temperature: 60 °C
Reaction time: 12 h
Yield: 78.7 %

Procedure:
2-Methoxyethanol (5.0 g) was added to a stirred suspension of sodium hydride (2.64 g of a 60% mineral oil suspension) in DHF (200 ml) at room temperature and under a atmosphere of argon. The stirred mixture was heated to 60° C. and then cooled to 5° C. A solution of 4-bromo-2-fluorobenzyl bromide (15 g) in dichlorobenzene (75 ml) was added over 15 minutes. The mixture stirred for 12 hours at room temperature, then for 1 hour at 60° C. and cooled. The mixture was diluted with iced water (600 ml) and extracted with ethyl acetate (3×200 ml). The combined extracts were washed with 2M hydrochloric acid (100 ml), water (2×100 ml), saturated brine (100 ml) and dried (MgSO4). Evaporation of the solvents gave an oil which was distilled using a short path distillation apparatus to give 1-(4-bromo-2-fluorobenzyloxy)-2-methyoxyethane (11.6 g), furnace temperature 125° C./0.01 bar; NMR (CDCl3): 3.40(3H, s), 3.5-3.7(4H, m), 4.58(2H, s) and 7.2-7.4(3H, m).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([CH2:14][NH:15][C:16](=[O:26])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:4][N:3]=1.[C-]#N.[K+].[N:30]12CCN(CC1)C[CH2:31]2>CS(C)=O.O>[C:31]([C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([CH2:14][NH:15][C:16](=[O:26])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:4][N:3]=1)#[N:30]
Reactant: C1CN2CCN1CC2
Reactant: COc1ccc(CC(=O)NCc2cnc(Cl)nc2NCC(C)(C)C)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CC(=O)NCc2cnc(C#N)nc2NCC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of 0.036 g (0.096 mmol) of N-[2-chloro-4-(2,2-dimethyl-propylamino)-pyrimidin-5-ylmethyl]-2-(4-methoxy-phenyl)acetamide, 0.013 g (0.192 mmol) of KCN and 0.011 g (0.096 mmol) of 1.4-diazabicyclo[2.2.2]octan in 1 ml of DMSO/H2O (85:15) is stirred for 45 minutes at 60° C. The reaction mixture is cooled to r.t. and subjected to preparative HPLC. N-[2-cyano-4-(2,2-dimethyl-propylamino)-pyrimidin-5-ylmethyl]-2-(4-methoxy-phenyl)-acetamide is obtained as a white solid.
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8](/[CH:11]=[CH:12]/[C:13]2[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=2[CH3:18])[CH:7]=1)=[O:5])C.[CH2:23]([CH2:25][NH2:26])[OH:24].N12CCCNC1=NCCC2>C1(C)C=CC=CC=1>[OH:24][CH2:23][CH2:25][NH:26][C:4]([C:6]1[O:10][N:9]=[C:8](/[CH:11]=[CH:12]/[C:13]2[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=2[CH3:18])[CH:7]=1)=[O:5]
Reactant: NCCO
Reactant: CCCCc1noc(C)c1/C=C/c1cc(C(=O)OCC)on1
Agent: C1CN=C2NCCCN2C1
Solvent: Cc1ccccc1
Product: CCCCc1noc(C)c1/C=C/c1cc(C(=O)NCCO)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
To a solution of 3-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-isoxazole-5-carboxylic acid ethyl ester (70 mg, 0.23 mmol) and ethanolamine (28 mg, 0.46 mmol) in toluene (1 mL) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (10 mg, 0.07 mmol) and the reaction stirred under argon overnight at room temperature. Then silica (1 g) was added and the mixture evaporated and the residue purified by chromatography (silica, dichloromethane:methanol=9:1 to 7:3) to afford the title compound (20 mg, 27%) which was obtained as a white solid. MS: m/e=320.1 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])C.[CH2:11]([N+:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH3:23])[CH3:22])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(O)C.O>[CH2:11]([CH:5]([CH2:6][CH2:7][CH2:8][CH3:9])[C:4]([O-:3])=[O:10])[CH3:12].[CH2:24]([N+:21]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([CH3:23])[CH3:22])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCC(=O)OCC
Agent: CCCCCCCCCC[N+](C)(C)CCCCCCCCCC
Solvent: O
Solvent: CCO
Product: CCCCC(CC)C(=O)[O-]

Procedure:
End grain pine wafers were weighed and then soaked with didecyldimethylammonium ethylhexanoate in ethanol/water until a weight gain of 35% was observed.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]1.Cl.[CH3:15]O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11]([O:13][CH3:15])=[O:12])[CH2:10][CH2:9]1
Reactant: CO
Reactant: O=C(O)C1(c2ccccc2Br)CC1
Agent: Cl
Product: COC(=O)C1(c2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(2-bromophenyl)cyclopropanecarboxylic acid (500 mg, 2.07 mmol) in MeOH (10 mL) was treated with a solution of concentrated aqueous HCl (0.5 mL). The resulting mixture was stirred for 16 hours at room temperature and then heated to reflux and stirred for a further 24 hours. The volatiles were evaporated and the residue was dissolved in EtOAc. The organic layer was washed with saturated solution of NaHCO3, brine and then dried over MgSO4. The solvent was removed in vacuo to give the title compound I4 (400 mg, 76%) as an orange oil; 1H NMR (400 MHz, CDCl3) δ 7.60-7.54 (m, 1H), 7.32-7.24 (m, 2H), 7.15 (m, 1H), 3.63 (s, 3H), 1.75 (d, J=3.1 Hz, 2H), 1.21 (q, J=4.0 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:16]#[CH:17])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C#CCCCCCC.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34]([N:37]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([O:46][CH3:47])[CH:44]=3)[C:39]([C:48]([C:50]3[CH:55]=[C:54]([O:56][CH3:57])[C:53]([O:58][CH3:59])=[C:52]([O:60][CH3:61])[CH:51]=3)=[O:49])=[CH:38]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1.IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:16]#[C:17][C:28]2[CH:33]=[CH:32][C:31]([S:34]([N:37]3[C:45]4[C:40](=[CH:41][CH:42]=[C:43]([O:46][CH3:47])[CH:44]=4)[C:39]([C:48](=[O:49])[C:50]4[CH:51]=[C:52]([O:60][CH3:61])[C:53]([O:58][CH3:59])=[C:54]([O:56][CH3:57])[CH:55]=4)=[CH:38]3)(=[O:35])=[O:36])=[CH:30][CH:29]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(S(=O)(=O)c3ccc(Br)cc3)c2c1
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(S(=O)(=O)c3ccc(C#CC4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)cc3)c2c1
Yield: 56 %

Procedure:
When tert-butyl-5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was substituted for 1-octyne and the product of Step C was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 56% yield, as yellow paste. 1H-NMR (CDCl3) 1.41 (s, 3H); 1.43 (s, 9H); 1.45 (s, 3H); 3.88 (s, 3H), 3.90 (s, 6H), 3.95 (s, 3H); 3.96 (d, 2H, J=11.58 Hz); 4.05 (d, 2H, J=11.45 Hz); 7.0 (dd, 1H, J=2.25, 8.82 Hz); 7.00 (s, 2H); 7.44 (broad s, 1H); 7.46 (d, 2H, J=8.7 Hz); 7.80 (d, 2H, J=8.61 Hz); 7.89 (s, 1H); 8.08 (d, 1H, J=8.82 Hz),
Reaction SMILES: [NH:1]([C:3]1[NH:4][CH2:5][CH2:6][N:7]=1)[NH2:2].Br.[OH-].[Na+].[C:11]1([CH2:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOCC>[C:11]1([CH2:17][C:18]([C:3]2([NH:1][NH2:2])[N:4]=[CH:5][CH:6]=[N:7]2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NNC1=NCCN1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: NNC1(C(=O)Cc2ccccc2)N=CC=N1

Procedure:
Phenylacetic acid (PAA), 0.037 moles (5g) was heated under reflux with an excess of SOCl2 for 60 minutes at a temperature of 75-80° C. After the reaction was completed, the excess SOCl2 was eliminated by vacuum evaporation, using a water pump (40-50° C.). This process was repeated two to three times, each time adding benzene to aid in elimination of SOCl2 and yielding phenylacetyl chloride (PAC). Then, 0.018 mole of 2-hydrazino-2-imidazoline.HBr (3.5 g) was suspended in ether and shaken with 2N NaOH (2-5 equivalents) on an ice bath, until it was completely dissolved. The PAC was then added dropwise very slowly from a funnel with vigorous shaking. Excess NaOH was present to drive the reaction to completion. After the addition of PAC, the mixture was stirred at 0C for an additional 15-30 minutes. The ether layer was washed with water, then with saturated NaHCO3. It was then dried over Na2SO4, filtered and was brought to complete dryness. The solid residue from the ether layer was then crystallized from an ethanol-water mixture (70-80% ethanol). The yield, was approximately 55% without subjecting the residual amide to further separation from the aqueous layer.
Reaction SMILES: [C:1](/[CH:4]=[CH:5]/[C:6]1[C:15]2[O:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([CH3:22])[C:11](=[O:23])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(O)=[O:2].S(Cl)([Cl:26])=O>C1(C)C=CC=CC=1>[Cl:26][C:1](/[CH:4]=[CH:5]/[C:6]1[C:15]2[O:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([CH3:22])[C:11](=[O:23])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(-c2ccccc2)oc2c(/C=C/C(=O)O)cccc2c1=O
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2)oc2c(/C=C/C(=O)Cl)cccc2c1=O
Yield: 69.7 %

Procedure:
A solution of 9.2 g of Intermediate III and 7.8 g of thionyl chloride in 75 ml of toluene was refluxed for 3 hours. After cooling to 20°-25° C. the resultant crystal was collected by suction filtration, washed with acetone and dried in vacuo to give 6.8 g of the title compound, m.p. (190) 196°-198° C. after recrystallization from toluene.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[CH3:46][C:34]1[N:33]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([C:21]3[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:27][CH:28]=2)[C:41]2[C:36]([C:35]=1[CH3:45])=[CH:37][C:38]([C:42](=[O:43])[NH:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=1)=[CH:39][CH:40]=2
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3cccc(C(F)(F)F)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 3-trifluoromethylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 557 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[N:16][C:17]([CH:20]([NH:22][C:23]([C:25]3[CH:33]=[CH:32][C:28]4[O:29][CH2:30][O:31][C:27]=4[CH:26]=3)=O)[CH3:21])=[CH:18][N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[O:29]1[C:28]2[CH:32]=[CH:33][C:25]([C:23]3[N:16]4[C:17]([CH:18]=[N:19][C:14]([NH:13][C:5]5[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=5)=[N:15]4)=[C:20]([CH3:21])[N:22]=3)=[CH:26][C:27]=2[O:31][CH2:30]1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc4c(c3)OCO4)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccc5c(c4)OCO5)n3n2)cc(OC)c1OC
Yield: 42.8 %

Procedure:
In a similar manner as described for Example 9, N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-1,3-benzodioxole-5-carboxamide (Intermediate 29) (61 mg, 0.134 mmol), and 1,2,4-triazole (55 mg, 0.80 mmol) in pyridine (2 mL) and phosphorous oxychloride (0.037 mL, 0.40 mmol) gave 7-(1,3-benzodioxol-5-yl)-5-methyl-N-(3,4,5-trimethoxy-phenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (25 mg, 43%) as a yellow solid. 1H NMR (CD3OD): δ8.99 (s, 1H), 7.87 (s, 1H), 7.84 (d, J=1.65 Hz, 1H), 7.04 (s, 2H), 6.95 (d, J=7.87 Hz, 1H), 6.04 (s, 2H), 3.80 (s, 6H), 3.74 (s, 3H), 2.56 (s, 3H). MS m/z 435 (M+1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[N+:12]([O-])([OH:14])=[O:13].S(=O)(=O)(O)O>>[CH3:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: Cc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
4-Trifluoromethyltoluene (12.8 g) was treated at 60°-70° C. with a mixture of concentrated nitric acid (25 ml) and concentrated sulphuric acid (25 ml) for 5 hours. The solution was poured onto ice (0.5 litres) and extracted with ether (3×100 ml). The combined ether extracts were washed with water, dried over sodium sulphate, filtered and evaporated to dryness to give 2-methyl-5-trifluoromethylnitrobenzene (14.8 g) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:23]1[C:28]([I:29])=[C:27]([CH:30]([Br:32])[CH3:31])[N:26]=[CH:25][N:24]=1>C1(C)C=CC=CC=1>[Br:32][CH:30]([C:27]1[N:26]=[CH:25][N:24]=[C:23]([NH:12][CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=2)[C:28]=1[I:29])[CH3:31]
Reactant: CC(Br)c1ncnc(Cl)c1I
Reactant: NCCc1ccc(OC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(Br)c1ncnc(NCCc2ccc(OC(F)(F)F)cc2)c1I
Temperature: 60 °C

Procedure:
In toluene (50 ml) were dissolved 2-(4-trifluoromethoxyphenyl)ethylamine (1.0 g) and triethylamine (1.0 g) then, 4-chloro-6-(1-bromoethyl)-5-iodopyrimidine (1.8 g) was added to the solution, and the mixture was heated at about 60° C. for 3 hours while stirring.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.COC1C=C(CC)C=CC=1O.[CH2:23]([O:30][C:31]1[CH:36]=[C:35]([CH2:37][CH3:38])[CH:34]=[CH:33][C:32]=1[OH:39])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][C:31]1[CH:36]=[C:35]([CH2:37][CH3:38])[CH:34]=[CH:33][C:32]=1[O:39][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[F:1])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCc1ccc(O)c(OCc2ccccc2)c1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: CCc1ccc(O)c(OC)c1
Product: CCc1ccc(Oc2ccc([N+](=O)[O-])cc2F)c(OCc2ccccc2)c1
Yield: 107.6 %

Procedure:
According to the procedure of example 20 (a) except substituting 1-fluoro-4-nitro-2-(trifluoromethyl)benzene for 3,4-difluoronitrobenzene (30.5 g; 192 mmol), and 2-methoxy-4-ethylphenol for 2-(benzyloxy)-4-ethylphenol (33.6 g; 147 mmol) the title compound (58.1 g; 100%) was prepared as a brown oil, used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Br[CH:32]([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:32]([CH3:34])[CH3:33])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: COC(=O)c1cccc(O)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cccc(OC(C)C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
To a solution of 0.20 g (0.468 mmol) of the product of Example 37 dissolved in 5.0 mL of DMF was added 0.26 mL (2.81 mmol) of 2-bromopropane and 1.16 g (8.43 mmol) of potassium carbonate. The reaction mixture was then heated to 80 degrees for 18 h, cooled to room temperature, diluted with ether and washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc-Hexanes (1:3) to provide 0.198 g (90%) of the desired product as a colorless oil. Electrospray Mass Spec: 470.3 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([CH2:68][C:69](O)=[O:70])=[C:64]([F:72])[CH:63]=1>CN(C)C(=O)C>[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([CH2:68][C:69]([NH:1][C:2]2[CH:3]=[CH:4][N:5]([CH3:27])[C:6]3[C:7]=2[CH:8]=[CH:9][C:10]2[N:19]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH2:18][CH:17]=[C:12]4[NH:13][C:14](=[O:16])[C:15]=3[C:11]=24)=[O:70])=[C:64]([F:72])[CH:63]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1F
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN1C=CC(NC(=O)Cc2ccc(Cl)cc2F)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Yield: 57 %

Procedure:
A stock solution of Example 23e and N,N-diisopropylethylamine (0.165 M and 0.47 M in N,N-dimethylacetamide, respectively, 275 μL, 0.042 mmol Example 23e and 0.13 mmol N,N-diisopropylethylamine), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.25 M in N,N-dimethylacetamide, 253 μL, 0.063 mmol), and 2-(4-chloro-2-fluorophenyl)acetic acid (0.40 M in N,N-dimethylacetamide, 125 μL, 0.05 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL per minute (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified using reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0126 g (57%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 8.06 (d, J=2.44 Hz, 1H), 7.56 (s, 1H), 7.45 (t, J=8.24 Hz, 1H), 7.40 (dd, J=8.54, 2.44 Hz, 1H), 7.31 (dd, J=9.77, 2.14 Hz, 1H), 7.25 (dd, J=8.24, 2.14 Hz, 1H), 7.17 (d, J=8.54 Hz, 1H), 6.97 (s, 1H), 6.78 (m, 2H), 6.50 (m, 2H), 4.58 (m, 2H), 4.05 (s, 3H), 3.77 (s, 2H). MS (APCI+) m/z 531.1 (M+H)+.
Reaction SMILES: [Na].[CH2:2]([C:5]([CH3:7])=[O:6])[CH2:3][CH3:4].[C:8]([O:15][CH2:16][CH3:17])(=[O:14])[C:9]([O:11]CC)=O>C(O)C>[O:11]=[C:9]([CH2:7][C:5](=[O:6])[CH2:2][CH2:3][CH3:4])[C:8]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCCC(C)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCC(=O)CC(=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.29 h
Yield: 64.4 %

Procedure:
Sodium (11.5 g, 500 mmol) was added to ethanol (130 mL) in portions at room temperature with vigorous stirring. After sodium got dissolved, the solution was cooled to 0° C. Methyl propyl ketone (53.0 mL, 500 mmol) was added dropwise and the stirring was continued for further 15-20 min. Diethyl oxalate (68.0 mL, 500 mmol) was added dropwise to the resulting solution at 0° C. and the stirring was continued for another 15 min at 0° C. The reaction mixture was then allowed to attain room temperature and the stirring was continued for further 12 h at this temperature. The reaction mixture was then kept in refrigerator for 24 h. The solvent was removed under vacuum at room temperature. The resulting residue was diluted with dil. hydrochloric acid on an ice bath and extracted the aqueous layer with diethyl ether (4×50 mL). The combined ether extracts were washed with water, brine, dried (Na2SO4) and concentrated under vacuum. The crude mass was chromatographed on silica gel using 3% ethyl acetate in pet. ether as eluent to yield the title compound (60.0 g, 64.5%).
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1.Cl.C(N=C=N)C.OS1C2C=CC=CC=2N=C1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:17](=[O:18])[CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]([C:1]34[CH2:10][CH:5]5[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]5)[CH2:8]3)[CH2:2]4)=[CH:21][CH:20]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: CCN=C=N
Agent: Cl
Agent: O[SH]1C=Nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)cc1
Reaction time: 8 h
Yield: 51.6 %

Procedure:
To a mixture of [4-(1-adamantyl)phenoxy]acetic acid (143.2 mg, 0.5 mmol), 4-aminobenzoic acid methyl ester (113.4 mg, 0.5 mmol), N-3-dimethylaminopropyl)-N′-ethyl carbodiimide HCl (EDC) (143.8 mg, 0.75 mmol) and 1-hydroxybenzothiazole (HOBt) (101.4 mg, 0.75 mmol) in DMF (6 mL) was added N,N-diisopropylethylamine, redistilled (DIPEA) (97.0 mg, 0.13 mL, 0.75 mmol). The mixture was stirred overnight, and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:Ethyl acetate:MeOH=6:3:1) to give 4-[2-(4-Adamantan-1-yl-phenoxy)-acetylamino]-benzoic acid methyl ester as a white solid (108.3 mg, 51.7% yield).
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])=[N:5][S:4][N:3]=1.[Cu](C#N)[C:15]#[N:16].O>CN1CCN(C)C1=O>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[C:2]([C:15]#[N:16])=[N:3][S:4][N:5]=1
Reactant: N#C[Cu]C#N
Reactant: Clc1ccccc1-c1nsnc1Br
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: N#Cc1nsnc1-c1ccccc1Cl
Yield: 53.3 %

Procedure:
In 1,3-dimethyl-2-imidazolidinone, were stirred 280 mg of 3-bromo-4-(2-chlorophenyl)-1,2,5-thiadiazole, and 180 mg of copper cyanide at 150° C. for 12 hours. After spontaneous cooling, the reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The diethyl layer was washed with dilute sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 120 mg of 3-(2-chlorophenyl)-4-cyano-1,2,5-thiadiazole. The obtained 3-(2-chlorophenyl)-4-cyano-1,2,5-thiadiazole (120 mg) was heated with 6 mL of 5% sodium hydroxide solution and 2 mL of ethanol, and refluxed for one hour. After spontaneous cooling, the reaction mixture was poured into a dilute hydrochloric acid solution, and the mixture was extracted with diethyl ether. The diethyl ether layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 100 mg of 4-(2-chlorophenyl)-1,2,5-thiadiazole-3-carboxylic acid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([NH:15]C(=O)OC(C)(C)C)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1.ClS([N:27]=[C:28]=[O:29])(=O)=O.O.C(=O)([O-])O.[Na+]>C(#N)C>[C:28](=[O:29])([O:1][CH2:2][CH2:3][CH:4]([NH2:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:6]=1)[NH2:27]
Reactant: CC(C)(C)OC(=O)NC(CCO)c1cccc(C(F)(F)F)c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NC(=O)OCCC(N)c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
Of the compound from Example 128A, 827 mg (2.59 mmol) were introduced in 100 ml of acetonitrile. A solution of 676 μl (7.77 mmol) of chlorosulphonyl isocyanate in 10 ml of acetonitrile was added dropwise at −15° C. After 5 min, 50 ml of water were added and the mixture was then stirred at 60° C. overnight. The reaction mixture was admixed with saturated aqueous sodium hydrogen carbonate solution and then extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. Drying of the residue in an HV gave 678 mg (quant.) of the title compound.