Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15]([OH:17])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[ClH:39].[F:40][C:41]1[CH:55]=[CH:54][CH:53]=[CH:52][C:42]=1[O:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C(N(CC)CC)C>CN(C=O)C.O>[ClH:39].[F:40][C:41]1[CH:55]=[CH:54][CH:53]=[CH:52][C:42]=1[O:43][CH2:44][CH2:45][N:46]1[CH2:47][CH2:48][N:49]([C:15](=[O:17])[CH2:14][CH2:13][C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:50][CH2:51]1
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Reactant: Fc1ccccc1OCCN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CCC(=O)N2CCN(CCOc3ccccc3F)CC2)cc(OC)c1OC
Temperature: 25 °C
Yield: 56.3 %

Procedure:
To a mixture of 3-(3,4,5-trimethoxyphenyl)propionic acid (0.36 g, 1.5 mmol), HOBt (0.24 g, 1.8 mmol), EDAC.HCl (0.34 g, 1.8 mmol) in DMF (4 mL) was added 1-[2-(2-fluoro-phenoxy)ethyl]piperazine (0.34 g, 1.5 mmol) and triethylamine (0.5 mL, 3.6 mmol). The mixture was then stirred at room temperature for a day, treated with water, and extracted with dichloromethane. The organic layer was washed with water and brine and then concentrated to dryness. The residue was dissolved in ethyl ether and was added with 2N HCl in ether (1 mL). The white solid was filtered and dried under vacuum to give the title compound (408 mg, 52%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:9]=[C:8]2[C:3]=1[C:4](=[O:31])[CH:5]=[C:6]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[N:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:32](O)(=[O:35])[CH2:33][CH3:34].CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:32](=[O:35])[CH2:33][CH3:34])[CH2:14][CH2:13]2)[N:9]=[C:8]2[C:3]=1[C:4](=[O:31])[CH:5]=[C:6]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[N:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCC(=O)O
Reactant: Cc1cc(N2CCNCC2)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: CCC(=O)N1CCN(c2cc(C)c3c(=O)cc(Nc4ccccc4)n(-c4ccccc4)c3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of 5-methyl-1-phenyl-2-phenylamino-7-piperazin-1-yl-1H-[1,8]naphthyridin-4-one (21.0 mg, 0.052 mmol), propionic acid (0.004 mL, 0.055 mmol), EDCI (11.9 mg, 0.062 mmol), DMAP (7.6 mg, 0.062 mmol), and NMM (0.006 mL, 0.062) in CH2Cl2 (0.8 mL) was stirred at room temperature overnight. The reaction was diluted with water and extracted with CH2Cl2. The combined organic extracts were washed with 0.5 N HCl and brine and concentrated in vacuo. The residue was purified by prep-TLC eluting with 100% EtOAc to give 5-methyl-1-phenyl-2-phenylamino-7-(4-propionyl-piperazin-1-yl)-1H-[1,8]naphthyridin-4-one (9.0 mg, 37%): LCMS RT: 2.29 min, MH+: 468.3.
Reaction SMILES: Br[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C([O-])(=[O:23])C.[Na+]>>[OH:23][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1
Reactant: CC(=O)[O-]
Reactant: O=c1c(CBr)c(-c2ccc(O)cc2)oc2ccccc12
Agent: [Na+]
Product: O=c1c(CO)c(-c2ccc(O)cc2)oc2ccccc12
Reaction time: 2 h
Yield: 65.9 %

Procedure:
A solution of 3-bromomethyl-2-(4-hydroxyphenyl)-4H-chromen-4-one (0.50 g, 1.5 mmol) and sodium acetate (1.24 g, 15.0 mmol) in ACOH (20 mL) was heated to reflux for 15 h. AcOH was removed and the residue was poured into water and extracted with EtOAc (100 mL). The organic phase was further washed with brine and dried over sodium sulfate. The residue was mixed with potassium carbonate (0.52 g) and MeOH (10 mL) and stirred for 2 h. AcOH (1.0 mL) was added and MeOH was removed. The residue was poured into water and the solid was washed additionally with water and hexane to give 3-(hydroxymethyl)-2-(4-hydroxyphenyl)-4H-chromen-4-one (0.265 g, 62.6%). MS (ES) m/z: 269.94 (M+1), 268.94 (M); Mp. 234-235° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]([C:36]([O:38][CH2:39][CH:40]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[C@H:26]([C:33]([OH:35])=O)[CH2:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30].[NH2:53][C@H:54]([C:67]([O:69][CH2:70][CH:71]=[CH2:72])=[O:68])[CH2:55][C:56]1[CH:61]=[CH:60][C:59]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[CH:58][CH:57]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:25]([C:36]([O:38][CH2:39][CH:40]1[C:52]2[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:42]2[C:41]1=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:37])[C@H:26]([C:33]([NH:53][C@H:54]([C:67]([O:69][CH2:70][CH:71]=[CH2:72])=[O:68])[CH2:55][C:56]1[CH:57]=[CH:58][C:59]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[CH:60][CH:61]=1)=[O:35])[CH2:27][O:28][C:29]([CH3:30])([CH3:31])[CH3:32]
Reactant: C=CCOC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@H](COC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 94.2 %

Procedure:
According to the general procedure for HBTU promoted coupling, 18.26 g Fmoc-Ser(tBu), 16.95 g HBTU, 11.95 g H-Tyr(tBu)-OAllyl and 26.10 ml DIPEA were reacted in a CYTOS® Lab System in anhydrous DMF at 45° C. and at a total flow rate of 32 ml/min at residence time of 1 min to yield 26.09 g crude material (yield based on HPLC: 96%) which was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([NH2:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1.[CH:15]1([CH2:20][C:21](O)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:1][O:2][C:3](=[O:14])[CH:4]([NH:13][C:21](=[O:22])[CH2:20][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1
Reactant: O=C(O)CC1CCCC1
Reactant: COC(=O)C(N)Cc1cccc(O)c1
Product: COC(=O)C(Cc1cccc(O)c1)NC(=O)CC1CCCC1
Yield: 54.9 %

Procedure:
12.5 g (54.3 mmol) of 2-amino-3-(3-hydroxy-phenyl)-propionic acid methyl ester was reacted with cyclopentyl acetic acid (6.97 g, 54.3 mmol) as described in general procedure A. The compound was purified using gradient elution with 10% to 100% ethyl acetate in hexanes to yield 9.1 g of 2-(2-cyclopentyl-acetylamino)-3-(3-hydroxy-phenyl)-propionic acid methyl ester.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[C:12]([O:18]C)[CH:11]=2)[CH2:5]1)([CH3:3])[CH3:2].[BrH:20]>>[BrH:20].[CH:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:18])[CH:11]=2)[CH2:5]1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C2CCCN(C(C)C)C2)cc1OC
Agent: Br
Product: CC(C)N1CCCC(c2ccc(O)c(O)c2)C1

Procedure:
A solution of 4.8 g of N-isopropyl-3-(3',4'-dimethoxyphenyl)-piperidine in 48 ml of 66% hydrobromic acid was refluxed for an hour and was evaporated to dryness. The residue was crystallized from isopropanol and then acetone to obtain 4.2 g of N-isopropyl-3-(3',4'-dihydroxyphenyl)-piperidine hydrobromide melting at 182° C.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[NH:6]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])[C:7]([NH2:9])=[NH:8].C1CCC(N=C=NC2CCCCC2)CC1.[CH3:34][S:35]([O:38][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[C:44]([C:49](=[NH:51])[NH2:50])[CH:45]=2)[CH:40]=1)(=[O:37])=[O:36]>N1C=CC=CC=1>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:34][S:35]([OH:38])(=[O:37])=[O:36].[NH:6]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([O:15][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[C:44]([C:49](=[NH:50])[NH2:51])[CH:45]=2)[CH:40]=1)=[O:14])[C:7]([NH2:9])=[NH:8]
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: N=C(N)Nc1cccc(C(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)O
Solvent: c1ccncc1
Product: N=C(N)Nc1cccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2)c1

Procedure:
To a solution of 4.7 g of m-guanidinobenzoic acid methanesulfonate in 50 ml of anhydrous pyridine, was added 4.4 g of DCC. To the mixture, while being cooled in ice and stirred, was added 5.0 of 6-amidino-2-naphthol methanesulfonate. After having been stirred for 24 hours, the reaction mixture was freed from the insolubles by filtration and the filtrate was mixed with ether. The oily substance which was formed was crystallized by adding ethyl acetate. Recrystallization from a mixture of methanol and ether gave 3.2 g of 6-amidino-2-naphthyl 3 -guanidinobenzoate dimethanesulfonate.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)[CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1C=CC(CCO)=[CH:23][CH:22]=1.C(OC(C1NC2C(C=1)=C(O)C=CC=2)=O)C>>[CH3:19][O:20][C:21]1[CH:2]=[CH:3][C:4]([CH2:1][CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)=[CH:23][CH:22]=1
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Reactant: COc1ccc(CCO)cc1
Agent: CCOC(=O)c1cc2c(O)cccc2[nH]1
Product: COc1ccc(CCOc2cccc3[nH]c(C(=O)O)cc23)cc1

Procedure:
4-[2-(4-Methoxy-phenyl)-ethoxy]-1H-indole-2-carboxylic acid (16l) is synthesized analogous to 16a from 2-(4-methoxy-phenyl)-ethanol and 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][O:8][C@H:7]([CH2:11][NH:12][C:13]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][N:21]=3)[CH:16]=[C:15]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[N:14]=2)[CH2:6]1)(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].I[CH2:42][CH3:43]>CN(C=O)C.CC(=O)OCC>[CH2:42]([N:32]1[CH2:33][CH2:34][CH:29]([C:26]2[CH:25]=[CH:24][C:23]([C:15]3[N:14]=[C:13]([NH:12][CH2:11][C@H:7]4[O:8][CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6]4)[C:22]4[C:17](=[N:18][CH:19]=[CH:20][N:21]=4)[CH:16]=3)=[CH:28][CH:27]=2)[CH2:30][CH2:31]1)[CH3:43]
Reactant: CCI
Reactant: CS(=O)(=O)N1CCO[C@H](CNc2nc(-c3ccc(C4CCNCC4)cc3)cc3nccnc23)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN1CCC(c2ccc(-c3cc4nccnc4c(NC[C@@H]4CN(S(C)(=O)=O)CCO4)n3)cc2)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of (R)—N-((4-(methylsulfonyl)morpholin-2-yl)methyl)-7-(4-(piperidin-4-yl)phenyl)pyrido[4,3-b]pyrazin-5-amine in (39.5 mg, 0.082 mmol) in DMF (5 mL) was added K2CO3 (22.6 mg, 0.164 mmol) and iodoethane (25.5 mg, 0.164 mmol) at room temperature. The reaction was stirred at 100° C. for 18 hours. After that, the reaction was dissolved in 50 mL of EA, washed with H2O (25 mL) and brine (25 mL), dried over Na2SO4 and concentrated, purified on TLC (CH2Cl2:MeOH=20:1) to give yellow solid. MS (m/z): 511 (M+H)+
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([OH:13])[CH:11]=[CH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:14][O:15][C:16](=[O:25])[C:17]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][C:18]=1O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[Si:1]([O:8][CH2:9][CH:10]([O:13][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([OH:23])[C:17]=1[C:16]([O:15][CH3:14])=[O:25])[CH:11]=[CH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)c1c(O)cccc1O
Reactant: C=CC(O)CO[Si](C)(C)C(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CC(CO[Si](C)(C)C(C)(C)C)Oc1cccc(O)c1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 24 %

Procedure:
A solution of alcohol from Example 16A (2.65 g, 13.1 mmol), methyl-2,6-dihydroxybenzoate (3.51 g, 20.9 mmol), PPh3 (3.34 g, 15.7 mmol), and TBF (20 mL) was cooled to 0° C. Diethylazodicarboxylate (2.51 g, 14.4 mmol) was added. The reaction was allowed to warm to room temperature and stir for 16 hours. The titled product (1.11 g, 24%) was obtained following silica gel column chromatography (10% ethyl acetate in hexanes).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.[CH:25]1[C:35]2[CH:34]=[CH:33][C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[C:30](=[CH:40][CH2:41][CH2:42][NH:43][CH3:44])[C:29]=2[CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH:25]1[C:35]2[CH:34]=[CH:33][C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[C:30](=[CH:40][CH2:41][CH2:42][N:43]([CH3:44])[C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:29]=2[CH:28]=[CH:27][CH:26]=1
Reactant: CNCCC=C1c2ccccc2C=Cc2ccccc21
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCC=C1c2ccccc2C=Cc2ccccc21)C(=O)CNC(=O)OC(C)(C)C

Procedure:
105 mg (0.60 mmol) of t-butoxycarbonylglycine, 111 mg (0.58 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride, 133 mg (0.51 mmol) of 3-(5H-dibenzo[a,d][7]annulen-5-ylidene)-N-methyl-1-propanamine and 0.08 ml (0.57 mmol) of triethylamine were stirred in 5 ml of dichloromethane at room temperature overnight. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. After extracting with dichloromethane, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.C[CH2:25][O:26][C:27](C)=[O:28]>CO.CS(C)=O.CCN(CC)CC.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH3:25][O:26][C:27]([C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1)=[O:28]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Reactant: CCOC(C)=O
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCC(CC)c1cc(C)nn2c(-c3sc(C(=O)OC)cc3C)c(C)nc12
Yield: 80 %

Procedure:
A solution of 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (1.00 g, 2.66 mmol) in CH3OH (12 mL), DMSO (18 mL), Et3N (2.0 mL) with Pd(OAc)2 (0.12 g, 0.538 mmol), dppf (0.937 g, 1.69 mmol) is reacted at CO atmosphere (100 psi) at 80° C. for 24 h. The reaction mixture is diluted with EtOAc (200 mL), washed with 0.1 M HCl (2×50 mL), brine (50 mL); dried with Na2SO4; filtered through silica gel and eluted with excess EtOAc. Purification of the crude material by chromatography gives the title compound (0.79 g, 2.12 mmol, 80%). 1H NMR (CDCl3): δ 0.89 (t, J=7.7 Hz, 6H), 1.75-1.93 (m, 4H), 2.15 (s, 3H), 2.50 (s, 3H), 2.53 (s, 3H), 3.32-3.42 (m, 1H), 3.91 (s, 3H), 6.72 (s, 1H), 7.73 (s, 1H). ES-MS (m/z): calcd for C20H25N3O2S (M+H)+: 372.5; found: 372.2.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:7][C:8]2[CH:14]=[C:13]([NH:15]/[C:16](/[CH3:21])=[CH:17]\[C:18]([O-:20])=O)[CH:12]=[CH:11][C:9]=2[N:10]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:7][C:8]2=[C:14]3[C:13](=[CH:12][CH:11]=[C:9]2[N:10]=1)[N:15]=[C:16]([CH3:21])[CH:17]=[C:18]3[OH:20]
Reactant: C/C(=C/C(=O)[O-])Nc1ccc2nc(-c3ccco3)[nH]c2c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cc1cc(O)c2c(ccc3nc(-c4ccco4)[nH]c32)n1
Reaction time: 0.25 h
Yield: 75.4 %

Procedure:
To a preheated (230°) solution of Dowtherm (500 ml) is added portion-wise 3-[[2-(2-furyl)-5-benzimidazolyl]amino]crotonate (38.5 g, 0.1 mole). After the addition is complete the reaction mixture is kept at 230° for 15 minutes, then decanted into a beaker to form, upon cooling, a tan precipitate. The precipitate is filtered and washed with hexane to give 20 g (74 percent) of tan solid. Recrystallization from CH3NO2 gives m.p. 280°-282°. Anal. Calcd. for C15H11N3O2 -1/4H2O: C, 66.78; H, 4.30; N, 15.58. Found: C, 66.56; H, 4.43; N, 15.40.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:4][CH:3]=1
Reactant: CCCCCC1C=Cc2ccc(F)c(F)c2O1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCCC1CCc2ccc(F)c(F)c2O1

Procedure:
51.0 g (0.21 mol) of 7,8-difluoro-2-pentyl-2H-chromene are hydrogenated at RT for 1 h in 510 ml of toluene in the presence of Pd/C (5% of Pd). The batch is evaporated to dryness: the crude product (yellowish liquid) can be used directly for the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([Sn](C)(C)C)[S:17][C:10]=12>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:2]3[CH:3]=[N:4][CH:5]=[N:6][CH:7]=3)[S:17][C:10]=12
Reactant: C[Sn](C)(C)c1cc2nccc(Cl)c2s1
Reactant: Brc1cncnc1
Solvent: Cc1ccccc1
Product: Clc1ccnc2cc(-c3cncnc3)sc12
Temperature: 25 °C
Yield: 50.5 %

Procedure:
Tereakis(triphenylphosphine)palladium (17 mg) was added to a solution of 5-bromopyrimidine (0.057 g, 0.36 mmole) and 7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.119 g, 0.36 mmole) in toluene (10 ml). The reaction mixture was stirred at 90□ C. overnight. After cooling to room temperature, the mixture was filtered, washed with CH2Cl2 and was partitioned between H2O (20 ml) and CH2Cl2 (2×20 ml). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 0-1% MeOH in CH2Cl2 to give white solid (0.045 g, 51%); 1H NMR (300 MHz, C6D6) δ9.25 (1H, s), 9.10 (2H, s), 8.64 (1H, d, J=5.1 Hz), 7.89 (1H, s), 7.34 (1H, d, J=5.1 Hz); ESIMS (MH+): 248.00.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:23][N+:24]([O-])=O)[CH2:10][P:11]([CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])(=[O:15])[O:12][CH2:13][CH3:14])=[CH:5][CH:4]=1.N.[H][H]>C(O)C.[Ni]>[NH2:24][CH2:23][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:10][P:11]([CH:16]([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22])(=[O:15])[O:12][CH2:13][CH3:14]
Reactant: [H][H]
Reactant: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccc(OC)cc1)OCC
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(CN)c1ccc(OC)cc1)OCC

Procedure:
A solution of 6.6 g of ethyl 2-(4-methoxyphenyl)-3-nitropropyl(diethoxymethyl)phosphinate in 50 ml of ethanol is added to 52 g of an 8% solution of ammonia in ethanol. To this are added 8 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give ethyl 3-amino-2-(4-methoxyphenyl)propyl(diethoxymethyl)phosphinate as a viscous oil, 31P=+44.5 ppm (CDCl3).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3]1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1I.CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu](I)I>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1CCCC(O)C1
Reactant: Fc1ccccc1I
Agent: I[Cu]I
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1CCCC(Oc2ccccc2F)C1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A reaction mixture of tert-butyl 3-hydroxycyclohexylcarbamate (4 mmol, 861 mg), 1-fluoro-2-iodobenzene (5 mmol, 585 4), copper iodide (0.4 mmol, 76 mg), 3,4,7,8-tetramethyl-1,10-phenanthroline (0.8 mmol, 190 mg) and cesium carbonate (10 mmol, 3.26 g) in toluene (5 mL) was stirred at 110° C. for overnight under argon. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated. The mixture was purified by silica gel column chromatography. The product, tert-butyl 3-(2-fluorophenoxy)cyclohexylcarbamate, was eluted off the column using 15% EtOAc in Hexane.
Reaction SMILES: C(O/[CH:4]=[CH:5]/[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[O:7])C>OS(O)(=O)=O>[CH3:16][O:15][C:11]1[CH:10]=[C:9]2[C:14]([CH:4]=[CH:5][C:6](=[O:7])[NH:8]2)=[CH:13][CH:12]=1
Reactant: CCO/C=C/C(=O)Nc1cccc(OC)c1
Agent: O=S(=O)(O)O
Product: COc1ccc2ccc(=O)[nH]c2c1
Reaction time: 1 h
Yield: 60.6 %

Procedure:
(2E)-3-(Ethyloxy)-N-[3-(methyloxy)phenyl]-2-propenamide (25 g; 0.113 mol) was dissolved in conc. H2SO4 and stirred for 1 h. The reaction mixture was poured onto ice and filtered. The crude product was washed with water and dried to yield the title compound (12 g; 60%) as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:31].[NH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:32][C:33]3[S:34][CH:35]=[CH:36][N:37]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:31]
Reactant: Nc1nccs1
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1nc(-c2cc(C(=O)Nc3nccs3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.2 %

Procedure:
To the solution of 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoic acid (1.41 g, 3.19 mmol) in DMF (50 mL) was added 2-aminothiazole (479 mg, 4.78 mmol), HBTU (1.33 g, 3.51 mmol) and Et3N (0.90 mL, 6.38 mmol). The reaction mixture was stirred at room temperature for 18 hours before was concentrated and applied to flash chromatography to afford the titled compound 0.99 g (60%). LC-MS m/z 525 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([Mg]Br)C.[CH3:15][C:16]1([CH3:24])[C:18]([CH3:20])([CH3:19])[CH:17]1[C:21](Cl)=[O:22]>ClCCl.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:21]([CH:17]1[C:18]([CH3:20])([CH3:19])[C:16]1([CH3:24])[CH3:15])=[O:22]
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: Clc1ccc2[nH]ccc2c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3ccc(Cl)cc23)C1(C)C
Yield: 42.5 %

Procedure:
A mixture of 5-chloroindole (0.30 g. 2.0 mmol), ethylmagnesium bromide (1.0 M solution in THF, 2.4 mL, 2.4 mmol), zinc chloride (1.0 M solution in Et2O, 2.4 mL, 2.4 mmol) and the product of Example 1A (3.0 mmol) in 15 mL of dichloromethane was processed as described in Example 1B to provide the title compound (0.23 g, 0.85 mmol, 43% yield). MS (DCI/NH3) m/z 276 (M+H)+.