Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8](Br)=[CH:9][CH:10]=1.C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1)CCC>CN(C=O)C.C(OCC)(=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>[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)=[CH:9][CH:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cnccn3)ccc1Oc1c(F)cc(O)cc12
Temperature: 110 °C

Procedure:
Pd(PPh3)4 (0.506 g, 0.438 mmol), (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (1.6 g, 4.38 mmol), and 2-(tributylstannyl)pyrazine (2.426 g, 6.57 mmol) were combined in 10 ml of DMF and heated in the microwave at 110° C. for two hours. The solution was diluted with ethyl acetate (50 mL) and washed twice with water. The organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified via silica gel column chromatography (RediSep 40 g column) using 10-100% 90/10/1 (CH2Cl2/MeOH/ammonia) in CH2Cl2 to afford (S)-2-amino-4′-fluoro-7′-(pyrazin-2-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol as a white solid. MS m/z=365.0 [M+H].
Reaction SMILES: [C:1]([O:8]N=C(C1C=CC=CC=1)C#N)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=O.Cl.Cl.[NH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27].O.C(Cl)Cl>O1CCOCC1>[C:1]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:8]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCCCCCN
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCCCCN
Reaction time: 12 h
Yield: 53.7 %

Procedure:
A solution of 2-(Boc-oxyimino)-2-phenylacetonitrile (226 mg, 0.92 mmol) in 1,4-dioxane (30 mL) was added via syringe pump (rate=8 mL/hr) to a stirred solution of 1,5 diaminopentane dihydrochloride (1 g, 5.52 mmol) and TEA (1 ml, 7.12 mmol) in 1:1 1,4-dioxane:water (40 mL) under inert atmosphere at room temperature. The reaction was stirred for 12 h and DCM (20 mL) was added to the reaction mixture. The organic phase was extracted and concentrated in vacuo. The yellow residue was dissolved in diethyl ether (15 mL) and 5% HCl solution added. The acidic solution was washed with diethyl ether and then the pH of the aqueous layer adjusted to pH 14 with 2.5M NaOH solution. Ethyl acetate (20 mL) was added and the organic layer was washed with brine (2×50 mL), and dried (MgSO4). The solvents were evaporated in vacua to yield N-Boc-cadaverine as a yellow oil (100 mg, 55%). HPLC/MS (Hydrophilic/TFA) Rt=6.17 min; ESI MS (+ve) m/z=203 [M+1H); calc. m/z for C10H22N2O2: 202.3 g/mol,
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH2:22][OH:23])=[N:12][C:11]=2[CH:24]([CH3:26])[CH3:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])N.[C:31]([N:48]=[C:49]=[O:50])(=[O:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>>[C:31]([NH:48][C:49](=[O:50])[O:23][CH2:22][C:13]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:24]([CH3:26])[CH3:25])[N:12]=1)(=[O:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCCCCCCC(=O)N=C=O
Reactant: CC(C)c1nc(CO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Agent: NC(=O)[O-]
Product: CCCCCCCCCCCCCCCC(=O)NC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1Cc1ccncc1
Yield: 50 %

Procedure:
The compound 89 (245 mg, 0.6 mmol) was converted to the carbamate with palmitoyl isocyanate (5 eq.) in the same manner as the example 66 to give the compound 95 (207 mg, 50%) as oil. Rf 0.40 (EtOAc). PMR (CDCl3): δH0.88 (3 H, t like, CH3),1.25 (24 H, bs, --CH2 --), 1.31 (6 H, d, J 7.0 Hz, (CH3)2CH), 1.59 (2 H, m, --CH2 --), 2.59 (2 H, t, J 7.8 Hz, --CH2CO--, 3.19 (1 H, sep, J 7.0 Hz, (CH3)2CH), 5.22 (2 H, s, NCH2), 5.27 (2 H, s, OCH2), 6.70 (2 H, d, J 1.6 Hz, arom 2- and 6-H), 6.76 (2 H, d-like, 4-pyridyl 2- and 6-H), 7.06 (1 H, t, J 1.6 Hz, arom 4-H), 7.35 (1 H, bs, NH), 8.46 (2 H, d-like, 4-pyridyl 3- and 5-H). IR (CHCl3)cm-1 3394 (NH), 1792 and 1764 (NCO), 1716 (NCOO). Elementary analysis (for C34H46N4O3SCl2) Calcd.: C, 62.69% H, 7.31% N, 8.12% S, 4.65% Cl, 10.28% Found: C, 61.89% H, 7.66% N, 8.41% S, 4.56% Cl, 9.65% hydrochloride of the compound 95 mp. 158-160° C. Elementary analysis (for C36H52N4O3SCl4) Calcd.: C, 56.69% H, 6.87% N, 7.35% S, 4.20% Cl, 18.59% Found: C, 55.85% H, 6.71% N, 7.64% S, 4.28% Cl, 18.66%
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]#N)[C:5]([N+:11]([O-])=O)=[CH:4][CH:3]=1.C(O)(=O)C.C(O)C.[K+].[Br-]>[Ni].CO.C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][NH:11][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc([N+](=O)[O-])c(CC#N)n1
Agent: [Ni]
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccc2[nH]ccc2n1
Reaction time: 4 h

Procedure:
A mixture of (6-methyl-3-nitro-2-pyridyl)-acetonitrile (1.83 g, 10.3 mmol),Raney nickel (0.20 g) and acetic acid/ethanol (3:7) was shaken under an atmosphere of hydrogen for 4 hours. The resulting mixture was filtered, and the filtrate was evaporated under reduced pressure. The residual oil was partitioned between saturated sodium hydrogen carbonate (25 mL) and ethyl acetate (25 mL). The organic layer was removed, and the aqueous layer was extracted with ethyl acetate (2×25 mL). The organic extracts were combined, dried (MgSO4), and evaporated under reduced pressure to yield a yellow solid. Column chromatography of this solid using silica gel (approx 50 g) and elution with 5% methanol in methylene chloride yielded Compound 7k (0.32 g, 2.4 mmol, 24%) as a tan solid: mp, 200°-202° C.; IR (KBr) 1610, 1570, 1465, 1445, 1405, 1290 cm-1 ; 1H NMR (DMSO-d6) δ 11.15 (br s, 1H), 7.65 (d,J=8.5 Hz, 1H), 7.54 (m, 1H), 6.95 (d, J=8.5 Hz, 1H), 6.45 (br m, 1H), 2.51 (s, 3H); 13 C NMR (DMSO-d6) 50.0, 145.7, 128.5, 126.6, 118.7, 116.0, 101.1, 24.2; Anal. calc'd for C8H8N2 ; C, 72.70; H, 6:10; N, 21.20; found: C, 72.22; H, 6.19; N, 21.25.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][O:8][C:7]2[CH:10]=[CH:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:6]=2[O:5]1.[N+:17]([O-])([OH:19])=[O:18].S(=O)(=O)(O)O.O>C(O)(=O)C>[CH3:1][O:2][CH2:3][CH:4]1[CH2:9][O:8][C:7]2[CH:10]=[C:11]([N+:17]([O-:19])=[O:18])[C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:6]=2[O:5]1
Reactant: COCC1COc2ccc(C(=O)O)cc2O1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COCC1COc2cc([N+](=O)[O-])c(C(=O)O)cc2O1
Reaction time: 0.5 h

Procedure:
The titled compound of Example 3 (0.788 g, 3.51 mmol) was dissolved in 2 ml of acetic acid, and added a mixture of nitric acid (3 ml) and sulfuric acid (3 ml), followed by stirring for 30 min. Then, to the reaction mixture was added 10 ml of water to give a solid, which was then fitered and washed with acetic acid and ether in a sequential order to prepare the titled compound (0.510 g, 54%).
Reaction SMILES: C([N:11]1[CH2:18][C:17](=[O:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.[BrH:20]>C(O)(=O)C>[BrH:20].[O:19]=[C:17]1[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1
Reactant: O=C1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Agent: Br
Solvent: CC(=O)O
Product: O=C1CN[C@H](C(=O)O)C1
Reaction time: 0.13 h

Procedure:
To 4.0 g. (0.015 mole) of N-carbobenzyloxy-4-keto-L-proline are added 20 ml. of hydrogen bromide in acetic acid (30-32%). The mixture is frequently swirled over a period of eight minutes. At the end of this period (effervescence has stopped), the yellow-orange solution is layered over with 250 ml. of ether, triturating the gummy product. The ether is discarded and the resulting tacky solid is triturated with fresh ether and finally with 50 ml. of acetonitrile to give 4-keto-L-proline, hydrobromide as a crystalline solid weighing 2.7 g. (85%), m.p. 153°-155° (dec.,), [α]D26 -49° (c, 1% in water).
Reaction SMILES: [CH2:1]([C:4]1([NH:14][NH2:15])[CH2:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].CCN(CC)CC.CN(C)[CH:25]=[CH:26][CH:27]=O>CC(O)C>[CH2:1]([C:4]1([N:14]2[CH:27]=[CH:26][CH:25]=[N:15]2)[CH2:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: CN(C)C=CC=O
Reactant: C=CCC1(NN)CCOC2(CCCC2)C1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C=CCC1(n2cccn2)CCOC2(CCCC2)C1
Reaction time: 48 h
Yield: 31 %

Procedure:
A solution of [9-(prop-2-en-1-yl)-6-oxaspiro[4.5]decan-9-yl]hydrazine (250 mg, 1.0 mmol) in 4 mL of i-PrOH were added Et3N and 3-dimethylaminoacrolein. The solution was refluxed for 3 h and then at 50° C. for 2 d. The solvent removed and the residue was purified on 25 g Biotage snap column, eluted with 0-18% EtOAc in Hex (12CV) to give 1-[9-(prop-2-en-1-yl)-6-oxaspiro[4.5]decan-9-yl]-1H-pyrazole (80 mg, 31% yield). LCMS m/z 247.1 (M+1) observed.
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.Cl.[C:15]1([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(O)CC(C)C>[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:3]2[NH:12][C:11](=[O:13])[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[N:4]=2)[CH2:25][CH2:24]1)(=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Reactant: O=C(c1ccccc1)N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)CCO
Product: O=C(c1ccccc1)N1CCN(c2nc3c(c(=O)[nH]2)CCCC3)CC1

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol), phenylpiperazin-1-ylmethanone hydrochloride (115.5 mg; 0.51 mmol) and triethylamine (141.3 μl; 1.02 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 9 (reaction time 6 h) and worked up. The crystals obtained after purification by column chromatography are dissolved in acetonitrile and water and freeze-dried; yield: 47 mg (27%), crystals;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl[CH2:18][C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH3:25][C:24]1[C:19]([CH2:18][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccnc1CCl
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Agent: Cl
Product: Cc1cc(C#Cc2cn(Cc3ncccc3C)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=303.2 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloromethyl-3-methyl-pyridine hydrochloride.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[N:16]=[C:15]([N:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]4[CH2:23][NH:24]C(=O)OC(C)(C)C)[C:14]([F:32])=[CH:13][N:12]=3)[CH:8]=2)[CH:3]=[N:2]1>C(O)(C(F)(F)F)=O>[NH2:24][CH2:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][N:17]1[C:15]1[C:14]([F:32])=[CH:13][N:12]=[C:11]([NH:10][C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[N:2][NH:1]3)=[CH:5][CH:6]=2)[N:16]=1
Reactant: CC(C)(C)OC(=O)NCC1CCCCN1c1nc(Nc2ccc3cn[nH]c3c2)ncc1F
Solvent: O=C(O)C(F)(F)F
Product: NCC1CCCCN1c1nc(Nc2ccc3cn[nH]c3c2)ncc1F
Yield: 78.7 %

Procedure:
A solution of tert-butyl (1-(2-(1H-indazol-6-ylamino)-5-fluoropyrimidin-4-yl)piperidin-2-yl)methylcarbamate (41 mg, 0.093 mmol) in TFA (4 mL) was stirred at room temperature for 60 min. TFA was removed in vacuo. The residue was purified by HPLC to give N-(4-(2-(aminomethyl)piperidin-1-yl)-5-fluoropyrimidin-2-yl)-1H-indazol-6-amine (25 mg) MS 342.3 (M+H);); UV 201.8, 246.8, 278.8 nm.
Reaction SMILES: [O:1]1[CH2:14][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][C:10]#[N:11])=[CH:7][CH:6]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CO>[OH:1][CH:2]([CH2:14][N:25]1[CH2:24][CH2:23][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:27][CH2:26]1)[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][C:10]#[N:11])=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#CCc1ccc(OCC2CO2)cc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CC(O)COc2ccc(CC#N)cc2)CC1
Yield: 70.1 %

Procedure:
A solution of 4-(2,3-epoxypropoxy)benzylcyanide (2.84 g, 15 mmol) and 1-(tert-butoxycarbonyl)piperazine (4.2 g, 22.5 mmol) in methanol (35 ml) was stirred at room temperature for 3 hours and the solvent was removed. The residue was dissolved in 200 ml of ethyl acetate, washed with water, dried over MgSO4 and concentrated. The obtained crude product was chromatographed on a silica gel column eluting with ethyl acetate. The obtained sticky material was triturated with hexane to give 3.95 g of the title compound, yield: 70.2%, mp. 98°-100° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][CH3:6])[CH3:2].C([Li])CCC.[C:15]([C:17]1[C:21]([CH:22]=[O:23])=[CH:20][N:19]([C:24]2[C:29]([Cl:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][C:25]=2[Cl:35])[N:18]=1)#[N:16].O>O1CCCC1.CCOCC>[C:15]([C:17]1[C:21]([CH:22]([OH:23])[C:6]#[C:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])=[CH:20][N:19]([C:24]2[C:29]([Cl:30])=[CH:28][C:27]([C:31]([F:32])([F:34])[F:33])=[CH:26][C:25]=2[Cl:35])[N:18]=1)#[N:16]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C=O
Reactant: CCOC(CC)OCC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C#CC(O)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N)OCC
Reaction time: 0.17 h

Procedure:
To a solution of propionaldehyde diethyl acetal (0.0192 g) in anhydrous tetrahydrofuran (2 ml) cooled to -78° C. under an atmosphere of nitrogen was added dropwise n-butyl lithium (621 μl, 2.5M in hexanes) and the mixture was stirred for 10 minutes. 3-Cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-formylpyrazole (0.05 g) was added and stirring continued for 30 minutes. The reaction mixture was poured into water (5 ml) and ether (5 ml). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (5 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white foam.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]=[C:7]2[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26])([OH:3])=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[F:47][C:48]([F:55])([F:54])[CH2:49][CH:50]([CH3:53])[CH2:51][NH2:52]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:26][O:25][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:15]=1[CH2:14][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([C:1](=[O:3])[NH:52][CH2:51][CH:50]([CH3:53])[CH2:49][C:48]([F:55])([F:54])[F:47])[CH:5]=2)[N:9]([CH3:13])[CH:8]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: CC(CN)CC(F)(F)F
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)O)cc23)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)NCC(C)CC(F)(F)F)cc23)c(OC)c1
Yield: 81.6 %

Procedure:
A solution of methyl 4-(5-carboxy-1-methylindol-3-ylmethyl)-3-methoxybenzoate (2.0 g), 4-dimethylaminopyridine (0.71 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.3 g), triethylamine (1.0 mL) and 4,4,4-trifluoro-2-methylbutylamine hydrochloride (1.2 g) in methylene chloride (28 mL) was stirred under a nitrogen atmosphere for 18 hours. The mixture was diluted with methylene chloride, washed (10% (w/v) hydrochloric acid, water and brine), dried (MgSO4), and evaporated. The resulting ivory foam was purified by flash chromatography, eluting with 1:1 ethyl acetate:hexane to afford methyl 3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)indol-3-ylmethyl]benzoate as a white powder (2.2 g, 82%); mp 168°-170° C.; partial NMR (300 MHz, CDCl3): 1.12 (d, 3H, CHCH3), 2.00 (m, 1H), 2.22 (m, 2H), 3.34-3.52 (m, 2H, NCH2), 3.75 (s, 3H, NCH3), 3.90 (s, 3H, CO2CH3), 3.93 (s, 3H, OCH3), 4.13 (s, 2H, CH2), 6.21 (t, 1H, NH), 6.82 (s, 1H, indole-H(2)), 8.02 (s, 1H, indole-H(4)).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19].CO.C(=O)(O)[O-].[Na+]>ClCCl.O>[OH:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)Cc1ccccc1Oc1cccc(OC)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1ccccc1Oc1cccc(O)c1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
Boron tribromide (12.89 g, 0.051 mol) was dissolved in dichloromethane (50 ml) and cooled to 0-5° C. A solution of methyl 2-(3-methoxyphenoxy)phenylacetate (7.0 g; 0.026 mol) in dichloromethane (80 ml) was added dropwise, with stirring over 1 hour. After stirring at 0°-5° C. for 20 minutes the mixture was added dropwise, with stirring to absolute methanol (100 ml) maintaining the temperature at 0°-5° C. The resulting solution was poured into water (250 ml) containing sodium bicarbonate (12 g), and the resulting mixture was extracted with ether (500 mls). The organic phase was washed with water (3×200 ml) and saturated brine (150 ml). After drying and filtration, evaporation of the ether solution gave methyl 2-(3-hydroxyphenoxy)phenylacetate (D) (6.12 g, 92.3% yield) as a brown gum. This material was suitable for use in subsequent steps without further purification. However, chromatography using mixtures of ether and hexane as eluant gave material of higher purity as a viscous golden oil which rapidly darkened on exposure to air.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](=O)[NH:3][CH:2]=1.[Cl:8][C:9]1[C:14](I)=[CH:13]N=CN=1.Cl.[CH:17]([O:20][C:21](=[O:31])[C@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:23])([CH3:19])[CH3:18]>>[ClH:8].[CH:17]([O:20][C:21](=[O:31])[C@H:22]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH2:23])([CH3:19])[CH3:18].[CH:17]([O:20][C:21](=[O:31])[C@H:22]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH:23][C:4]1[C:5]([CH2:13][CH2:14][C:9]2[CH:26]=[CH:25][CH:24]=[CH:22][CH:21]=2)=[CH:6][N:1]=[CH:2][N:3]=1)([CH3:19])[CH3:18]
Reactant: Clc1ncncc1I
Reactant: O=c1ccnc[nH]1
Agent: CC(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: CC(C)OC(=O)[C@H](Cc1ccccc1)Nc1ncncc1CCc1ccccc1

Procedure:
L-Phenylalanine isopropyl ester hydrochloride was prepared by Method LLL. 4(3H)-Pyrimidinone (Aldrich) was sequentially converted via Methods N and O to 4-chloro-5-iodopyrimidine. L-Phenylalanine isopropyl ester hydrochloride and 4-chloro-5-iodopyrimidine were coupled via Method P and the coupled product sequentially converted via Methods OOO and X to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)#[N:16].O>C1(C)C=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>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([C:21]2[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=2)[C:15]#[N:16])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)ccc2c1Cl
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2cccc(C#N)c2)nc2cc(F)ccc2c1Cl

Procedure:
Prepared according to procedure F using 2,4-dichloro-7-fluoro-3-methylquinoline (500 mg, 2.17 mmol), 3-cyanophenylboronic acid (319 mg, 2.17 mmol), Pd(PPh3)4 (251 mg, 0.22 mmol) in toluene:water (10 mL:4 mL) and heating at reflux overnight. After purification, 3-(4-chloro-7-fluoro-3-methylquinolin-2-yl)benzonitrile was obtained as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][C@H:19]([CH3:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C@@H:30]3[O:35][C:34]4=[N:36][C:37]([N+:39]([O-:41])=[O:40])=[CH:38][N:33]4[CH2:32][CH2:31]3)=[CH:24][CH:23]=2)[CH2:17][C@H:16]1[CH3:42])=O)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:21][C@H:19]1[CH2:20][NH:15][C@H:16]([CH3:42])[CH2:17][N:18]1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][C@@H:30]2[O:35][C:34]3=[N:36][C:37]([N+:39]([O-:41])=[O:40])=[CH:38][N:33]3[CH2:32][CH2:31]2)=[CH:26][CH:27]=1
Reactant: C[C@@H]1CN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)[C@@H](C)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)[C@@H](C)CN1
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (4 ml) was added to a dichloromethane solution (4 ml) of (2R,5S)-2,5-dimethyl-4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester (1.31 g), and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure to afford the title compound as a brown amorphous compound (1.35 g).
Reaction SMILES: Br.Br[CH:3]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([F:19])[CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1)=O.[NH2:20][C:21]([NH2:23])=[S:22].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[F:19][C:15]1[CH:14]=[C:13]([C:3]2[S:22][C:21]([NH2:23])=[N:20][C:4]=2[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=2)[CH:18]=[CH:17][N:16]=1
Reactant: NC(N)=S
Reactant: Cc1cccc(C(=O)C(Br)c2ccnc(F)c2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccc(-c2nc(N)sc2-c2ccnc(F)c2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a mixture of 2-bromo-2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone hydrobromide and thiourea (3.03 g, 39.8 mmol) in acetonitrile (50 mL) was added triethylamine (5.2 mL, 37.3 mmol), and the mixture was stirred for 2 hours at 80° C. Aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the deposited solid was collected by filtration. The resulted solid was washed with water, then, dried. The crude crystal was recrystallized from ethanol to obtain a title compound (3.67 g, yield 35%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14].[H-].[Na+].[CH3:27]I.[NH4+].[Cl-]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:5][N:6]([CH3:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: CI
Reactant: COC(=O)[C@@H](CNc1ccccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](CN(C)c1ccccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
A solution of 1.0 eq of 177 in 20 mL of dry DMF was stirred at rt as 1.3 eq of NaH (60% in mineral oil) was added. After bubbling ceased (about 10 min), 1.1 eq of MeI was slowly added. After 18 h, 50 mL of sat. aq. NH4Cl was added to the reaction mixture. The mixture was extracted with EtOAc (3×50 mL). The combined organics were dried over MgSO4 and filtered. The filtrate was rotary evaporated. The crude material was flash chromatographed on silica using 20% EtOAc/hexanes as eluant. After concentration and drying under vacuum the fractions containing product afforded intermediate 178.