Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C@@H:3]([OH:11])[CH2:4][C:5](=[O:10])[C:6]=1[CH2:7][C:8]#[CH:9].[CH2:12](N(CC)CC)[CH3:13].C(Br)=C.Cl>C1C=CC=CC=1.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>[CH3:1][C:2]1[C@@H:3]([OH:11])[CH2:4][C:5](=[O:10])[C:6]=1[CH2:7][C:8]#[C:9][CH:12]=[CH2:13]
Reactant: C#CCC1=C(C)[C@@H](O)CC1=O
Reactant: CCN(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=CBr
Agent: Cl
Solvent: c1ccccc1
Product: C=CC#CCC1=C(C)[C@@H](O)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10 Grams of (+)-(S)-2-methyl-3-propargylcyclopent-2-en-4-one-1-ol was dissolved in 100 ml of benzene. Thereto were added successively 3.85 g of tetrakis(triphenylphosphine)palladium, 1.27 g of cuprous iodide and 13.5 g of triethylamine. 150 Grams of vinyl bromide was promptly added to the resultant mixture. The mixture was stirred under nitrogen atmosphere at room temperature overnight. Thereafter, the mixture was poured on dilute hydrochloric acid. A benzene layer was recovered from the mixture, and the water layer was further extracted with benzene. The benzene layers were mixed, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Methanol was added to the residue, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate=3:1) to obtain 7.5 g of (+)-(S)-2-methyl-3-(pent-4-en-2-ynyl)-cyclopent-2-en-4-one-1-ol.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[O:10][CH:11]=[CH:12][C:4]=2[CH2:3]1.[Cl:13][C:14]1[CH:15]=[C:16](F)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[CH:12]=[CH:11][O:10][C:5]2=3)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CN1CCC(O)c2occc2C1
Reactant: Fc1ccc(Cl)c(Cl)c1
Product: CN1CCC(Oc2ccc(Cl)c(Cl)c2)c2occc2C1

Procedure:
The same method as in Example 1 was conducted using 5-methyl-5,6,7,8-tetrahydro-4H-furo[3,2-c]azepin-8-ol (Reference Example 21) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=[CH:7]2.C(Cl)(=O)C(Cl)=O.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:14])[CH:8]=[CH:7]2
Reactant: O=C(O)c1ccc2cccc(Br)c2n1
Reactant: C1CCNC1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(c1ccc2cccc(Br)c2n1)N1CCCC1
Yield: 94.2 %

Procedure:
This compound (365 mg, 94% yield) as a tan crystalline solid was prepared similarly to that described in Example 167a, using 8-bromoquinoline-2-carboxylic acid (Princeton BioMolecular Research, Monmouth Junction, N.J.; 320 mg, 1.27 mmol), oxalyl chloride (2.54 mmol), and pyrrolidine (0.10 mL, 1.27 mmol) as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.59 (1H, d, J=8.4 Hz), 8.23 (1H, dd, J=7.6, 1.2 Hz), 8.11 (1H, dd, J=8.2, 1.0 Hz), 8.01 (1H, d, J=8.6 Hz), 7.63 (1H, t, J=7.8 Hz), 3.98 (2H, t, J=6.5 Hz), 3.61 (2H, t, J=6.5 Hz), 1.95 (4H, m). m/z (ESI, +ve) 307/307 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([Cl:25])[C:6]=1F)[CH3:2].[CH:28]([NH2:32])([CH2:30][CH3:31])[CH3:29]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([Cl:25])[C:6]=1[NH:32][CH:28]([CH2:30][CH3:31])[CH3:29])[CH3:2]
Reactant: CCC(C)N
Reactant: CCOC(=O)c1cc(F)c(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(Cl)c1F
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(F)c(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(Cl)c1NC(C)CC
Yield: 167.5 %

Procedure:
4-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-3-chloro-2,5-difluorobenzoic acid ethyl ester (Example 2c, 1.95 g, 4.81 mmol), sec-butylamine (30 mL, 296 mmol), and dimethyl sulfoxide (20 mL) are heated in a sealed glass tube at 110° C. for 24 hours. The reaction mixture is evaporated, and purification by column chromatography (1:8, ethyl acetate/hexanes) provides the title compound as a yellow syrup (3.69 g). MS EI: m/z 458 (MH+).
Reaction SMILES: [CH3:1][S:2]SC.[CH:5]1[C:18]2[C:9](=[CH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1>C(#N)C.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][S:2][C:17]1[C:18]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: c1ccc2cc3ccccc3cc2c1
Reactant: CSSC
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Product: CSc1c2ccccc2cc2ccccc12

Procedure:
For example, in acetonitrile, dimethyl disulfide shows an irreversible first oxidation peak at 1.05 V vs Ag/O.1M AgNO3 in acetonitrile reference electrode using the technique of cyclic voltimetry. The oxidation peak of anthracene is about 400 mV more positive than that for dimethyl disulfide. Consequently, pursuant to this invention, dimethyl disulfide can be selectively oxidized electrolytically in the presence of anthracene to produce the organothiated product, 9-methylthioanthracene, in very good yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].[CH2:26]([NH2:28])[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([NH:28][CH2:26][CH3:27])=[O:21])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2]
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCNC(=O)c1cnc(N2CCC[C@@H](Oc3ccccc3OCC)C2)nc1

Procedure:
(R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N-ethylpyrimidine-5-carboxamide was prepared from (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid and ethylamine using Amidation Method 1 (HATU). 1H NMR (300 MHz, DMSO-d6) δ 8.72 (s, 2H), 8.29 (app t, 1H), 7.08 (d, 1H), 6.91 (m, 3H), 4.31 (m, 1H), 4.21 (app d, 1H), 3.85 (m, 5H), 3.25 (m, 2H), 2.08 (m, 1H), 1.83 (m, 2H), 1.57 (m, 1H), 1.23 (t, 3H), 1.12 (t, 3H). MS (ES+) 371.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24]([NH:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:25])[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.C(O)(=O)C.[Br:37]Br.C(O)(=O)C>O>[Br:37][C:7]1[C:2]([OH:1])=[C:3]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24]([NH:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:25])[CH2:20][CH2:19]3)[C:4]2=[N:5][CH:6]=1
Reactant: BrBr
Reactant: O=C(Nc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(O)ccnc32)CC1
Solvent: CC(=O)O
Solvent: O
Product: O=C(Nc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c2ncc(Br)c3O)CC1
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a solution of the title compound from Example 263 (0.34 grams) and glacial acetic acid (10 mL) was added a 0.7 M bromine-acetic acid solution (4 mL) at 25° C. under N2. After 10 minutes, water was added and the resulting solid was filtered and washed with water several times and dried to give the title compound (Yield 0.31 grams, 67%, MH+ 527).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16](=[O:22])[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C@H:10]([CH3:15])[C:11]([O:13]C)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:16](=[O:22])[N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)[C@H:10]([CH3:15])[C:11]([OH:13])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](C(=O)O)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of the product from Step A (0.404 g, 1.29 mmol) in THF (30 mL) and water (10 mL) was added lithium hydroxide (96.0 mg, 4.0 mmol). After stirring at room temperature for 3 h, the reaction was quenched with 1N hydrochloric acid. The organic phase was separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo to give the desired product.
Reaction SMILES: [Cl:1][CH:2]([Cl:16])[C:3]([O:5][N:6]=[C:7]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:8](Cl)=[O:9])=[O:4].[NH2:17][C@@H:18]1[C:49](=[O:50])[N:20]2[C:21]([C:33]([O:35][CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])=[C:22]([CH2:25][S:26][C:27]3[S:28][C:29]([CH3:32])=[N:30][N:31]=3)[CH2:23][S:24][C@H:19]12>C(OCC)(=O)C.C1OC1C>[Cl:1][CH:2]([Cl:16])[C:3]([O:5][N:6]=[C:7]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:8]([NH:17][C@@H:18]1[C:49](=[O:50])[N:20]2[C:21]([C:33]([O:35][CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])=[C:22]([CH2:25][S:26][C:27]3[S:28][C:29]([CH3:32])=[N:30][N:31]=3)[CH2:23][S:24][C@H:19]12)=[O:9])=[O:4]
Reactant: O=C(Cl)C(=NOC(=O)C(Cl)Cl)c1cccs1
Reactant: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](N)[C@H]3SC2)s1
Agent: CC1CO1
Solvent: CCOC(C)=O
Product: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)C(=NOC(=O)C(Cl)Cl)c4cccs4)[C@H]3SC2)s1

Procedure:
A solution of 2-dichloroacetoxyimino-2-(thien-2-yl)acetyl chloride 0.585 g.) in ethyl acetate (5 ml.) was added to a stirred suspension of diphenylmethyl 7β-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethylceph-3-em-4-carboxylate (1 g.) in ethyl acetate (10 ml.) and propylene oxide (1 ml.) at 20°. After 30 minutes all the solid had dissolved. The solution was washed with 2 N-hydrochloric acid, saturated sodium bicarbonate solution, water and brine, dried and concentrated to give crude diphenylmethyl 7β-[2-dichloroacetoxyimino-2-(thien-2-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethylceph-3-em-4-carboxylate (syn-isomer) as a solvated foam (1.567 g.) λmax. (EtOH) 267.5 nm (E11 240), τ values (CDCl3) include 3.00 (singlet, --CHPh2), 3.75 (singlet; CHCl2) and 7.35 (singlet; CH3).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8].[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=2)[C:7]([NH:9][CH3:10])=[O:8])[CH2:20][CH2:19]1
Reactant: OCCN1CCNCC1
Reactant: CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(N2CCN(CCO)CC2)ccc1[N+](=O)[O-]

Procedure:
A solution of 5-fluoro-N-methyl-2-nitrobenzamide, 1-(2-hydroxyethyl)piperazine, and Hunig's base in 20 mL of DMF was stirred at room temperature over the weekend. The resulting mixture was rotavaped to dryness, and the residue was purified by flash column SF40-150 at 2%-10% MeOH/CH2Cl2. Product came out at 7% MeOH/CH2Cl2. MS(ES) m/e 309 [M+H].
Reaction SMILES: [F:1][C:2]1([F:6])[CH2:5][NH:4][CH2:3]1.[Cl:7][C:8]1[CH:9]=[N:10][N:11]([C:13]2([C:16]3[NH:33][C:19]4=[N:20][C:21]([N:24]5[CH2:29][CH2:28][CH2:27][C@@H:26]([C:30](O)=[O:31])[CH2:25]5)=[CH:22][CH:23]=[C:18]4[N:17]=3)[CH2:15][CH2:14]2)[CH:12]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl>[Cl:7][C:8]1[CH:9]=[N:10][N:11]([C:13]2([C:16]3[NH:33][C:19]4=[N:20][C:21]([N:24]5[CH2:29][CH2:28][CH2:27][C@@H:26]([C:30]([N:4]6[CH2:5][C:2]([F:6])([F:1])[CH2:3]6)=[O:31])[CH2:25]5)=[CH:22][CH:23]=[C:18]4[N:17]=3)[CH2:15][CH2:14]2)[CH:12]=1
Reactant: FC1(F)CNC1
Reactant: O=C(O)[C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1
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: O=C([C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1)N1CC(F)(F)C1
Reaction time: 2 h
Yield: 43.3 %

Procedure:
3,3-Difluoroazetidine (33 mg, 0.2 mmol) was added to a mixture of (R)-1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylic acid (100 mg, 0.25 mmol), diisopropylethylamine (0.1 mL, 0.77 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (118 mg, 0.31 mmol) in anhydrous dichloromethane (5 mL) at room temperature. The reaction mixture was stirred for 2 h, then partitioned between dichloromethane and water. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via preparative TLC to afford the title compound (40 mg, 43% yield). MS (ES+) (M+H) 462.2; LCMS retention time 2.163 minutes (Method N1). 1H NMR (300 MHz, CDCl3) δ 1.17-1.39 (m, 1H), 1.71-2.24 (m, 7H), 2.35-2.58 (m, 1H), 2.83-3.13 (m, 2H), 4.04-4.78 (m, 6H), 6.63 (d, 1H), 7.62 (s, 2H), 7.69-7.80 (m, 1H), 9.15 (br s, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[CH:13]1[C:25]2[CH:24]([CH2:26][O:27][C:28](ON3C(=O)CCC3=O)=[O:29])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1>CC(C)=O.C(OCC)(=O)C>[CH:13]1[C:25]2[CH:24]([CH2:26][O:27][C:28]([NH:2][CH2:3][C:4]([NH2:6])=[O:5])=[O:29])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: NCC(N)=O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.3 %

Procedure:
To 2-amino-acetamide hydrochloride (Compound 31, 10.0 g, 90.5 mmol), a 10% aqueous solution of sodium carbonate (600 ml) and acetone (250 ml) were added; next, under ice cooling, a solution of N-(9-fluorenylmethoxycarbonyloxy)succinimide (30.5 mg, 90.5 mmol) in acetone (250 ml) was added drop by drop. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure; the residue obtained was dissolved in ethyl acetate, the organic phase was sequentially washed with a 2N aqueous solution of citric acid, aqueous sodium hydrogen carbonate and saturated brine, after which it was dried with magnesium sulfate. The solid was filtered and concentrated under reduced pressure, after which crystallization from methanol was conducted to yield the desired 2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-acetamide (Compound 32; 27.7 g, quant).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15].O>CN(C=O)C>[CH3:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCCn1ccnc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Imidazole 1 g (0.015 mol) was dissolved in dry DMF 50 mL under argon atmosphere. After a NaH mineral oil dispersion (60%) 0.68 g (0.017 mol) was added, the mixture was heated at 80° C. for 70 min. After cooling to room temperature, 1-Bromo-2-(2-methoxyethoxy)-ethane (1), 2.75 g (0.015 mol), was added, then stirred overnight. The reaction was poured into water, extracted by CHCl3, washed by water, dried over Na2SO4, then dried (Rotavap) until an oily residue remained. The crude product was purified with silica gel flash column chromatography with an eluant of CHCl3: CH3OH=20:1. 1.69 g (70% yield) of the product (2) was obtained as a colorless oil. As an alternative to column chromatography, product (2) is purified by vacuum distillation.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=O)[CH:4]=[CH:5][NH:6][CH:7]=[CH:8][C:9]#[N:10].[OH-].[Na+].CCCCCC.CC(C)=[O:24]>CO>[F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([NH2:10])=[O:24])=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: N#CC=CNC=CC(=O)C(F)(F)F
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCC
Product: NC(=O)c1cnccc1C(F)(F)F
Yield: 65.6 %

Procedure:
3-[(4,4,4-Trifluoro-3-oxo-1-butenyl)amino]-2-propenenitrile (a low-polar compound IIa; 1.90 g, 10 mmol) was dissolved in methanol (15 ml), and sodium hydoxide (600 mg, 15 mmol) was added. The mixture was heated under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a eluting solvent: hexane/acetone=1/1) to obtain 1.25 g (yield 65.6%) of the title compound.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>C(O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:6][CH:5]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)CSc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
1.36 g of potassium hydroxide was dissolved in 38 ml ethanol by heating, allowed to cool, mixed with 3.8 g of 4-bromobenzenethiol, further with 3.8 g of silica gel and 2.96 ml of t-butyl bromoacetate, followed by stirring at room temperature for 4 hours. Silica gel was filtered off and the filtrate was concentrated and purified via column chromatography on silica gel (ethyl acetate:hexane=1:20) to give t-butyl [(4-bromophenyl)thio]acetate (5.98 g, 98.6%).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14](N)=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].N([O-])=[O:24].[Na+]>O.S(=O)(=O)(O)O>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]([OH:24])=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC(=O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reaction time: 8 h

Procedure:
Add 2 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxamide to 4.7 ml of concentrated sulfuric acid while cooling on ice and then add thereto a solution of 0.78 g of sodium nitrite in 2 ml of water slowly and dropwise at a temperature not exceeding 7° C. Allow the resulting mixture to stand overnight; dilute with from 4 to 5 ml of concentrated sulfuric acid and then mix it (while cooling with ice) with 0.39 g of sodium nitrite in 1 ml of water. Allow the thus-prepared solution to stand at a temperature of 0° to 5° C for 2 days in a refrigerator and then pour it onto ice. Vacuum filter to separate formed precipitate and chromatograph with chloroform/ethanol (9:1) on a silica gel column to obtain 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid [m.p. 250° to 252° C].
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH2:25][CH3:26])[N:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[F:27].[Li+].[OH-]>O.C1COCC1>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([C:17]#[C:16][C:15]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[C:5]([F:27])[CH:6]=3)=[N:11][CH:12]=[N:13][C:14]=2[CH2:25][CH3:26])=[CH:23][CH:22]=1
Reactant: CCc1ncnc(-c2ccc(C(=O)OC)c(F)c2)c1C#Cc1ccc(N)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ncnc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(N)nc1
Temperature: 25 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 17.8 g (47.3 mmol) 4-[5-(6-amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-fluoro-benzoic acid methyl ester using 3.97 g (94.6 mmoL) LiOH in 30 mL water and 300 mL THF. The reaction mixture is stirred over night at RT. The solvent is removed under reduced pressure and the residie is taken up in water. Aqueous 1 M HCl is added until pH 5 is reached. The precipitated product is filtered off and washed with ACN. After drying 17.1 g (85%) of the desired product are obtained a solid material.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[NH2:31][C:32]1[C:33](=[O:48])[N:34]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[F:47])[C:35](=[O:39])[NH:36][C:37]=1[NH2:38]>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16](=[O:18])[NH:31][C:32]2[C:33](=[O:48])[N:34]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[F:47])[C:35](=[O:39])[NH:36][C:37]=2[NH2:38])=[CH:13][CH:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1[nH]c(=O)n(Cc2ccccc2F)c(=O)c1N
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(CC(=O)Nc2c(N)[nH]c(=O)n(Cc3ccccc3F)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91 %

Procedure:
A solution of (4-tert-butoxycarbonylamino-phenyl)-acetic acid in N,N-dimethylformamide under argon at 25° C. was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The reaction was stirred at 25° C. for 5 min. At this time, the reaction was treated with 5,6-diamino-3-(2-fluoro-benzyl)-1H-pyrimidine-2,4-dione and 4-dimethylarninopyridine. The reaction was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was diluted with water (75 mL) and then acidified to pH=5 with a 1.0N aqueous hydrochloric acid solution. The resulting solid was collected by filtration, rinsed well with water and cold ether, and dried in vacuo to afford (4-{[6-amino-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl]-methyl}-phenyl)-carbamic acid tert-butyl ester (4.10 g, 91%) as a yellow solid; LRMS for C28H32FN5O5 (M+H)+ at m/z=538.
Reaction SMILES: [C:1]1([OH:8])[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.[N:9]([CH2:12][CH3:13])=[C:10]=[O:11].C(N(CC)CC)C>O1CCOCC1>[OH:7][C:4]1[CH:5]=[CH:6][C:1]([O:8][C:10](=[O:11])[NH:9][CH2:12][CH3:13])=[CH:2][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCNC(=O)Oc1ccc(O)cc1

Procedure:
Benzene-1,4-diol Compound 25a was reacted with isocyanato-ethane and a catalytic amount of triethylamine in 1,4-dioxane at room temperature to provide ethyl-carbamic acid 4-hydroxy-phenyl ester Compound 25b.
Reaction SMILES: C([C@H](NC(=O)C1C=CC=C(S(C)(=O)=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:44]=[C:45]([S:47]([CH3:50])(=[O:49])=[O:48])[CH:46]=1)[C:41]([OH:43])=O.[CH:51]12[CH2:57][CH:54]([CH2:55][CH2:56]1)[CH2:53][CH:52]2[NH:58][C:59](=[O:74])[C@H:60]([CH3:73])[CH2:61][C@H:62]([OH:72])[C@@H:63]([NH2:71])[CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>>[CH2:64]([C@H:63]([NH:71][C:41](=[O:43])[C:40]1[CH:44]=[C:45]([S:47]([CH3:50])(=[O:49])=[O:48])[CH:46]=[C:38]([O:37][CH3:36])[CH:39]=1)[C@@H:62]([OH:72])[CH2:61][C@H:60]([C:59](=[O:74])[NH:58][CH:52]1[CH2:53][CH:54]2[CH2:57][CH:51]1[CH2:56][CH2:55]2)[CH3:73])[C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Reactant: COc1cc(C(=O)O)cc(S(C)(=O)=O)c1
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cccc(S(C)(=O)=O)c1)C(=O)NCCC(C)(C)C
Product: COc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NC2CC3CCC2C3)cc(S(C)(=O)=O)c1

Procedure:
Prepared in an analogous manner to E1 from 3-methoxy-5-methylsulfonylbenzoic acid (D15) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D4).