Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28]Br)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:28][CH2:27][CH2:26][NH:25][C:23]([O:22][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:24]
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Yield: 97.3 %

Procedure:
A solution of 2.69 grams (0.010 mole) of 2,6-dichloro-4-phenylmethoxyphenol (known compound), 2.38 grams (0.010 mole) of (tert-butoxy)-N-(3-bromopropyl)carboxamide (commercially available) and 1.52 grams (0.011 mole) of potassium carbonate in 40 mL of DMF was stirred at ambient temperature during a four-day period. After this time the reaction mixture was shaken in diethyl ether and water, and the separated organic layer was washed with one portion of water and with one portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 4.15 grams of the subject compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:18])[C@H:12]([C@H:14]([CH2:16][CH3:17])[CH3:15])[NH2:13])[CH3:9].C(OC(=O)[C@H]([C@H](CC)C)N)C.C(N)C1C=CC=CC=1.[CH3:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][CH2:50][C:51](Cl)=[O:52].COCCCCCCCCCCCC(Cl)=O>>[CH3:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][CH2:50][C:51]([NH:13][C@H:12]([C:11]([O:10][CH2:8][CH3:9])=[O:18])[C@H:14]([CH2:16][CH3:17])[CH3:15])=[O:52]
Reactant: COCCCCCCCOCCCC(=O)Cl
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)CC
Agent: COCCCCCCCCCCCC(=O)Cl
Solvent: NCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H](NC(=O)CCCOCCCCCCCOC)[C@@H](C)CC

Procedure:
The title compound is prepared by the method of Example 14 using L-isoleucine ethyl ester trifluoroacetate [the title product of Example 44] as a reactant instead of benzylamine, and using an equivalent amount of 4-[(7-methoxyheptyl)oxy]butanoyl chloride [the title product of Example 100] instead of 12-methoxy-1-docecanoyl chloride [the title product of Example 11].
Reaction SMILES: CO.[ClH:3].Cl.Cl.[OH:6][C:7]1[CH:31]=[CH:30][C:10]([CH2:11][NH:12][C:13]([NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[NH:17])=[NH:14])=[CH:9][CH:8]=1.[CH3:32][C:33]([CH3:35])=O>>[ClH:3].[CH2:19]([NH:18][C:16]1[NH:15][C:13]([NH:12][CH2:11][C:10]2[CH:9]=[CH:8][C:7]([OH:6])=[CH:31][CH:30]=2)=[N:14][C:33]([CH3:35])([CH3:32])[N:17]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CC(C)=O
Reactant: CCCCCCCCCCCNC(=N)NC(=N)NCc1ccc(O)cc1
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCCNC1=NC(C)(C)N=C(NCc2ccc(O)cc2)N1

Procedure:
25 ml of methanol, 40 ml of acetone and 0.1 ml of concentrated hydrochloric acid were added to 2.0 g (4.5 mmol) of N1-(4-hydroxybenzyl)-N5-undecyl-biguanide dihydrochloride, and the mixture was refluxed for 24 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (8:1.5)), and then recrystallized with 80% aqueous acetonitrile to obtain 0.73 g of colorless crystals having a melting point of 110 to 112° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C@H:8]([CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:9][N+]([O-])=O)[C:3]=1[F:17].C[O-].[Na+].S(=O)(=O)(O)[OH:22]>CO.C(OCC)(=O)C.[Cl-].[NH4+]>[F:17][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:8]([CH2:13][CH2:14][CH:15]=[CH2:16])[CH:9]=[O:22]
Reactant: C=CCC[C@H](C[N+](=O)[O-])c1cccc(F)c1F
Reactant: O=S(=O)(O)O
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C=CCC[C@H](C=O)c1cccc(F)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 138.3 %

Procedure:
In a 250 mL round-bottomed flask was dissolved (S)-1,2-difluoro-3-(1-nitrohex-5-en-2-yl)-benzene (4.14 g, 17.2 mmol) in methanol (21 mL) under nitrogen. After cooling to 0° C., sodium methoxide (4.12 mL, 18.0 mmol) was added via syringe. After stirring at 0° C. for 30 min, the temperature was lowered to −60° C. Conc. sulfuric acid (2.93 mL, 54.9 mmol) in 21 mL methanol was added dropwise. The resulting milky mixture was stirred at −60 to −20° C. for 4 h. It was diluted with ethyl acetate and saturated ammonium chloride solution. The layers were separated. The aqueous layer was extracted with ethyl acetate (2×40 mL). The combined organic layers were washed with brine, dried, and concentrated to a give tan oil (4.8 g), which was dissolved in chloroform (124 mL) Water (31 mL) was added followed by slow addition of trifluoroacetic acid (31 mL). The mixture was stirred at rt overnight for 18 h. The layers were separated. The aqueous layer was extracted with methylene chloride. The combined organic layers were dried and concentrated to give a light yellow oil (5 g, 100%). This was directly carried onto next reaction immediately.
Reaction SMILES: C([O:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][N:25]=[CH:24]4)[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[NH:26]1[C:27]2[C:23](=[CH:22][C:21]([NH:20][CH:17]3[CH2:18][CH2:19][N:14]([CH2:13][C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:31][CH:30]=4)[CH2:15][CH2:16]3)=[CH:29][CH:28]=2)[CH:24]=[N:25]1
Reactant: c1ccc(COc2ccc(CN3CCC(Nc4ccc5[nH]ncc5c4)CC3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(CN2CCC(Nc3ccc4[nH]ncc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.4 %

Procedure:
N-{1-[4-(Benzyloxy)benzyl]-4-piperidyl}-N-(1H-5-indazolyl)amine (Example 142, 33 mg) and palladium-charcoal (10 mg) were suspended in ethanol (3 ml), and the suspension was stirred under a hydrogen atmosphere of 1 atm at room temperature for 18 hr. The reaction mixture was filtered through Celite, and the filtrate was then concentrated to give the title compound (21 mg, yield 82%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([O:11][CH2:12][CH2:13][N:7]3[CH:6]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18][CH:5]23)[CH:10]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35].C>>[CH3:37][O:36][C:32]1[CH:31]=[C:30]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([O:11][CH2:12][CH2:13][N:7]4[CH:6]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18][CH:5]34)[CH:10]=2)[CH:29]=[C:28]([O:27][CH3:26])[C:33]=1[O:34][CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC2c3cc(Br)cc4c3N(CCO4)C2CC1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: C
Product: COc1cc(-c2cc3c4c(c2)C2CCN(C(=O)OC(C)(C)C)CCC2N4CCO3)cc(OC)c1OC
Yield: 74.8 %

Procedure:
Tert-butyl 5-(3,4,5-trimethoxyphenyl)-1,2,6b,7,8,10,11,11a-octahydro-9H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole-9-carboxylate (609 mg, 75%) was prepared via coupling of the tert-butyl 5-bromo-1,2,6b,7,8,10,11,11a-octahydro-9H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole-9-carboxylate (671 mg, 1.64 mmol) with 3,4,5-trimethoxyphenyl boronic acid (522 mg, 2.46 mmol) as illustrated above using the typical procedure for Suzuki coupling. 1H NMR (CDCl3, 300 MHz) δ1.49 (s, 9H), 1.80-2.20 (m, 4H), 2.80-2.91 (m, 1H), 3.25 (d, 1H, J=10.8 Hz), 3.42-3.70 (m, 1H), 3.83 (s, 3H), 3.88 (s, 6H), 4.40-4.51 (m, 2H), 6.69 (s, 2H), 6.82 (s, 1H), 6.86 (s, 1H) ppm. CIMS (Methane) m/z=497 [MH]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[NH:28]1[CH:32]=[N:31][N:30]=[N:29]1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[N:7]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:29]3[N:30]=[N:31][CH:32]=[N:28]3)[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: c1nnn[nH]1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCCl)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCCCn3ncnn3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=444.3 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-tetrazole.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19].[H-].[Na+]>CN(C=O)C>[CH3:21][O:20][C:18](=[O:19])[CH2:17][N:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:15]=[CH:14][C:7]1=2
Reactant: COC(=O)CBr
Reactant: O=C1CCCc2cc([N+](=O)[O-])ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Temperature: 60 °C
Yield: 90 %

Procedure:
7-Nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (375 mg, 1.82 mmol) and methyl bromoacetate (417 mg, 2.73 mmol) were dissolved in anhydrous DMF. Sodium hydride (60% in mineral oil, 146 mg, 3.64 mmol) was added, and the mixture was heated to 60° C. for 2 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water, washed once with water, and concentrated to a brown oil. Preparative TLC (50% EtOAc/hexane) afforded (7-Nitro-2-oxo-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-acetic acid methyl ester as a yellow solid, 454 mg. (90% yield) 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.12-8.18 (m, 1H), 7.51-7.56 (m, 1H), 4.60 (s, 2H), 3.62 (s, 3H), 2.93-3.00 (m, 2H), 2.05-2.20 (m, 4H); MS (m/e) 279 (M+1).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][NH:23][CH3:24].CO>>[CH3:22][N:23]([CH3:24])[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cn1
Reactant: CNC
Solvent: CO
Product: COc1ccc(N(C)c2nc(N(C)C)nc3ccccc23)cn1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine (69 mg, 0.23 mmol) and 2.0 M dimethylamine in methanol (4 ml, 8 mmol) by a procedure similar to example 122 (51%). 1H NMR (CDCl3): 8.02 (d, J=2.7 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.38-7.34 (m, 2H), 6.93 (d, J=8.4 Hz, 1H), 6.75-6.66 (m, 2H), 3.94 (s, 3H), 3.51 (s, 3H), 3.30 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C:3]1=[O:17].[BH4-].[Na+].C(Cl)(Cl)Cl.[NH4+].[Cl-]>CO.CCOC(C)=O>[OH:17][CH:3]1[C:2]([CH3:18])([CH3:1])[CH2:6][CH2:5][N:4]1[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: CC1(C)CCN(C(=O)OCc2ccccc2)C1=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)CCN(C(=O)OCc2ccccc2)C1O
Temperature: -10 °C
Yield: 95.8 %

Procedure:
In a 500 ml flask was dissolved phenylmethyl 3,3-dimethyl-2-oxo-1-pyrrolidinecarboxylate (0.0494 mol, 12.2 g) in 100 ml methanol. The mixture was cooled to −10° C. and sodium borohydride (0.247 mol, 9.35 g) was added slowly in portions with stirring, maintaining an internal temperature below −5° C. After the addition TLC (90:10 CHCl3:EtOAc) confirmed reaction was complete. The mixture was poured onto 500 ml saturated aqueous NH4Cl with crushed ice and stirred 16 hours, after which time the aqueous phase was extracted with Et2O (2×200 ml). The organics were dried over MgSO4, filtered and concentrated yielding 11.8 g (96%) of phenylmethyl 2-hydroxy-3,3-dimethyl-1-pyrrolidinecarboxylate as a clear oil which was used without further purification. LCMS (ESI+)=232 m/z ([M-OH]+). 1H NMR (400 MHz, CDCl3)— rotamers δ 7.39-7.33 (m, 5H), 5.25-5.14 (m, 2H), 4.99 and 4.92 (s, 1H), 3.61-3.38 (m, 2H), 1.97-1.91 (m, 1H), 1.62-1.56 (m, 1H), 1.12 (s, 3H), 1.02 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)[CH3:13]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][N:11]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)c1ccccc1
Product: CC(=NNc1ccc([N+](=O)[O-])cc1)c1ccccc1

Procedure:
10.2 g of acetophenone -p-nitrophenylhydrazone (melting point: 186.5-188.0° C.) obtained by equimolar reaction of p-nitrophenylhydrazine and acetophenone was subjected to Vilsmeir reaction with phosphorus oxychloride and dimethylformamide to obtain 11.8 g of 1-(p-nitrophenyl)-3-phenylpyrazole-4-carboxyaldehyde (melting point: 208.5-211.0° C.) having the following structural formula. ##STR300##
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH2:9][C:10](=O)[C:11]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].O.[NH2:21][NH2:22]>C(O)C>[C:1]([C:3]1[C:8]2[CH2:9][C:10](=[N:21][NH2:22])[C:11]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: NN
Reactant: N#Cc1cccc2c1CC(=O)c1ccc(F)cc1S2
Solvent: CCO
Solvent: O
Product: N#Cc1cccc2c1CC(=NN)c1ccc(F)cc1S2

Procedure:
The mixture of 1.0 g of 9-cyano-3-fluoro-10,11-dihydrodibenzo[b,f]thiepin-11-one, 1.1 g of 100% hydrazine hydrate and 16 ml of ethanol was heated under reflux for 4.5 hours. The reaction mixture was concentrated to about one-fifth. After cooling, crystals was collected by filtration, there was obtained 9-cyano-3-fluoro-10,11-dihydrodibenzo[b,f]thiepin-11-one hydrazone having a melting point of 178°-179° C. in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([OH:24])=[N:12][CH:13]=[CH:14]2)=[N:9]1.FC(F)(F)S(O[CH2:31][C:32]([F:35])([F:34])[F:33])(=O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11](=[O:24])[N:12]([CH2:31][C:32]([F:35])([F:34])[F:33])[CH:13]=[CH:14]2)=[N:9]1
Reactant: Oc1nccc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc12
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Product: O=c1c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2ccn1CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(2-chlorophenyl)-3-(4-chlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-ol (I-9A-1b: 150 mg, 0.421 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (107 mg, 0.463 mmol) and CS2CO3 (151 mg, 0.463 mmol) in DMF (2.1 ml) were stirred overnight at room temperature. The reaction mixture was extracted from saturated aqueous NaHCO3 with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), concentrated in vacuo, and then purified on a Biotage™ Flash 12M column using 0–40% ethyl acetate in hexanes as eluant to give the title compound 9A-1 (145 mg, 79%) as a colorless solid: +ES MS (M+1) 438.3; 1H NMR (CD2Cl2) δ 7.70 (d, J=6.2 Hz, 1H), 7.59–7.56 (m, 1H), 7.52–7.43 (m, 3H), 7.38–7.34 (m, 2H), 7.29–7.25 (m, 3H), 5.03 (br s, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]([OH:18])=O)[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11]3[CH2:30][CH2:31][C:32](=[O:33])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.[NH:63]1[CH2:68][CH2:67][S:66][CH2:65][CH2:64]1>CN(C)C=O>[O:19]=[C:13]1[N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=2)[C:11]2[CH2:30][CH2:31][C:32](=[O:33])[C:10]=2[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[N:14]1[CH2:15][C:16](=[O:18])[N:63]1[CH2:68][CH2:67][S:66][CH2:65][CH2:64]1
Reactant: C1CSCCN1
Reactant: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)N2CCSCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidin-3(2H,4H,5H)-yl)acetic acid (example 4, 30 mg, 66 μmol) and triethylamine (30 μL, 0.22 mmol) in N,N-dimethylformamide (1.25 mL) is treated with N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (21 mg, 66 μmol) and stirred at room temperature for 15 min. This mixture is then added to a solution of thiomorpholine (13 mg, 0.13 mmol) in N,N-dimethylformamide (0.25 mL) and stirred for 72 h. The mixture is filtered and the filtrate is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of methanol in water, 0.1% NH3). Yield: 20 mg; ESI mass spectrum [M+H]+=541; Retention time HPLC: 1.17 min (001_CA03).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[C:23]([CH3:46])=[N:24][N:25](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:26]=4)[CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[ClH:47]>>[ClH:47].[ClH:47].[CH2:1]([NH:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[C:23]([CH3:46])=[N:24][NH:25][CH:26]=4)[CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)N1CCN(c2ccnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4C)cc23)CC1
Agent: Cl
Product: CCNC(=O)N1CCN(c2ccnc3ccc(-c4c[nH]nc4C)cc23)CC1

Procedure:
118 mg N-ethyl-4-[6-(3-methyl-1-trityl-1H-pyrazolyl)-4-quinolyl]-1-piperazine carboxamide obtained in Example 180 and 1.5 mL of 5 N hydrochloric acid were reacted in the same manner as in Example 163, to give 72 mg of the title compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)=[O:7])=[CH:18][CH:17]=1
Reactant: Clc1ccccc1
Reactant: O=C(O)c1cccc(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 3-fluorobenzoic acid (1.00 g, 7.14 mmol), thionyl chloride (3 mL, 41.1 mmol) and a drop of DMF and the reaction was refluxed for 2 h. The excess thionyl chloride was then distilled off and the residual thionyl chloride was removed on the pump. Chlorobenzene (5 mL, 50 mmol) and aluminum trichloride (1.050 g, 7.85 mmol) were added to the reaction mixture. The reaction mixture turned yellow in color on addition of AlCl3. The reaction mixture was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane.
Reaction SMILES: [CH2:1]([C@H:8]([NH:39]C(=O)OC(C)(C)C)[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:39][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2cccnc2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2cccnc2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of Example 148D (0.108 g, 0.17 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.5 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, and the reaction was partitioned between ethyl acetate and diluted NaHCO3 solution. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH3:25])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1COCC1>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](=[S:35])[NH:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Solvent: C1CCOC1
Product: CNC(=S)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 151 %

Procedure:
To a solution of 3-(benzyloxy)-N,9,9-trimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.40 g, 1.17 mmol, 1.0 equiv) in THF (12 mL) under a nitrogen atmosphere, was added Lawesson's reagent (0.28 g, 0.70 mmol, 0.6 equiv). The yellow solution was then heated to 50° C. (oil bath). After stirring for 1 h, the reaction was cooled to ambient temperature and concentrated in vacuo. The crude product was purified by silica gel chromatography (20-100% ethyl acetate/hexane) to provide the title compound (0.38 g, 90% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.19 (s, 1H), 7.45-7.57 (m, 2H), 7.29-7.42 (m, 3H), 5.25 (s, 2H), 3.93-4.12 (m, 4H), 3.17 (d, J=5.04 Hz, 3H), 1.62 (s, 6H); LCMS (ES+, (M+H)+) m/z 360.19.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([C:10]#[C:11][Si](C)(C)C)[CH:3]=1>CN(C=O)C.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:7][C:8]=1[F:9])[NH:6][CH:11]=[CH:10]2
Reactant: C[Si](C)(C)C#Cc1cc(Br)c(F)cc1N
Agent: [Cu]I
Solvent: CN(C)C=O
Product: Fc1cc2[nH]ccc2cc1Br
Temperature: 100 °C

Procedure:
CuI (0.932 g, 4.89 mmol) was added to a solution of 4-bromo-5-fluoro-2-[(trimethylsilyl)ethynyl]aniline (0.700 g, 2.45 mmol) in DMF (25 mL). The resulting suspension was heated at 100° C. for 1 h. The reaction mixture was partitioned between 10% aqueous Na2S2O3 and Et2O. The aqueous layer was extracted with Et2O. The combined organic layers were washed with 5 N aqueous NaOH and brine, dried (Na2SO4), filtered, and concentrated. The crude product was used in the next step without further purification.