Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:47]=[CH:46][C:45]([C:48]4[C:52](C#N)=[CH:51][S:50][CH:49]=4)=[CH:44][CH:43]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19].[N:55]1([CH2:60][CH2:61][CH2:62][NH:63][C:64]2C3SC=C(C4C=CC(O)=CC=4)C=3[N:67]=[CH:68][N:69]=2)[CH2:59][CH2:58][CH2:57][CH2:56]1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:43]=[CH:44][C:45]([C:48]4[C:52]5[N:67]=[CH:68][N:69]=[C:64]([NH:63][CH2:62][CH2:61][CH2:60][N:55]6[CH2:56][CH2:57][CH2:58][CH2:59]6)[C:51]=5[S:50][CH:49]=4)=[CH:46][CH:47]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19]
Reactant: Oc1ccc(-c2csc3c(NCCCN4CCCC4)ncnc23)cc1
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CCCOc3ccc(-c4csc5c(NCCCN6CCCC6)ncnc45)cc3)s1)CC2

Procedure:
The title compound 78 was prepared as a TFA salt in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 78B: 1H NMR (DMSO-d6): δ 12.82 (s, 1H), 9.53 (s, 1H), 8.52 (s, 1H), 8.22 (s, 1H), 8.03-8.07 (m, 1H), 8.01 (d, J=7.98 Hz, 1H), 7.69 (d, J=8.59 Hz, 1H), 7.79 (d, J=7.98 Hz, 1H), 7.67 (d, J=7.36 Hz, 1H), 7.32-7.49 (m, 4H), 7.01 (d, J=8.9 Hz, 2H), 4.84 (s, 2H), 4.04 (t, J=6.29 Hz, 2H), 3.73 (t, J=5.83 Hz, 2H), 3.18-3.24 (m, 4H), 3.01-3.05 (m, 4H), 1.78-2.07 (m, 6H). ESI (+)/MS: 831 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].I[CH2:25][CH3:26]>>[CH3:1][O:2][C:3](=[O:23])[CH:4]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:25][CH3:26])[CH:5]([CH3:7])[CH3:6]
Reactant: CCI
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)C(C)C)cc1
Product: CC#CCOc1ccc(S(=O)(=O)N(CC)C(C(=O)OC)C(C)C)cc1
Yield: 88.1 %

Procedure:
According to the procedure of Example 5, 0.350 g (1.032 mmol) of 2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-methyl-butyric acid methyl ester and 0.25 mL (3.097 mmol) of iodoethane provided 0.334 g of 2-[(4-but-2-ynyloxy-benzenesulfonyl)-ethyl-amino]-3-methyl-butyric acid methyl ester as a white solid. Electrospray Mass Spec 368.4 (M+H)+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26].O.[NH2:35][NH2:36].C(=O)([O-])O.[Na+]>CN(C=O)C>[C:27]1([CH:25]([C:24]2[C:3]3[C:4](=[O:23])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:20])[F:21])[CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:36][N:35]=2)[CH3:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C(=O)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O)c1ccccc1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1ccccc1)c1n[nH]c2c1c(=O)n(-c1cccc(OC(F)(F)F)c1)c1ncccc21
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(2-phenylpropionyl)-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one (276 mg, 0.61 mmol) produced in Synthesis Example 32 in DMF (3 mL) was added hydrazine monohydrate (purity of 80%, 100 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution, and an oily substance was collected. To the oily substance was added isopropyl ether, and the mixture was heated. Then the resulting matter was allowed to stand to a room temperature for crystallization. The resulting crystal was separated by filtration and dried to give 3-(1-phenylethyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one as a form of crystal (140 mg, yield 51%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12](=[O:47])[CH2:13][CH:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[NH2:32])=[CH:27][C:26]=1[O:34][CH2:35][CH2:36][C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1)(=[O:24])=[O:23])[C:15](N(OC)C)=[O:16])([CH3:10])([CH3:9])[CH3:8]>C(OCC)C.C(OCC)(=O)C>[C:7]([O:11][C:12](=[O:47])[CH2:13][CH:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[NH2:32])=[CH:27][C:26]=1[O:34][CH2:35][CH2:36][C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1)(=[O:24])=[O:23])[CH:15]=[O:16])([CH3:10])([CH3:8])[CH3:9]
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(C(N)=O)cc1OCCc1cccc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC(C=O)NS(=O)(=O)c1ccc(C(N)=O)cc1OCCc1cccc2ccccc12
Temperature: -65 °C
Reaction time: 4.5 h

Procedure:
To a 65° C. solution of lithium aluminum hydride (0.37 ml, 1M in diethyl ether) in diethyl ether (5 mL) was added a solution of 3-[4-carbamoyl-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonylamino]-N-methoxy-N-methyl-succinamic acid tert-butyl ester (0.20 g, 0.34 mmol) in diethyl ether (5 mL). The reaction was stirred at −65° C. for 4.5 hours. The reaction was then diluted with ethyl acetate (100 mL) and washed with 10% potassium hydrogen sulfate (25 mL) and saturated sodium chloride (25 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 3-[4-carbamoyl-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester as a clear oil. MS(APCI) m/z 525.1(M−H)
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.Br[CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>>[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[C:4]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Reactant: N#Cc1ccc(CBr)cc1
Agent: Cl
Product: Cc1c(-c2cccnc2)n(Cc2ccc(C#N)cc2)c2ccccc12

Procedure:
3-Methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 1) and 4-bromomethyl-benzonitrile are processed according to the method described in Example 25 to give 4-(3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile. 1H NMR (400 MHz, MeOD) δ ppm 2.32 (s, 3H), 5.43 (s, 2H), 6.99 (d, J=8.6 Hz, 2H), 7.13-7.21 (m, 1H), 7.25 (ddd, J=7.6, 1.3 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.54 (dd, J=8.0, 4.9 Hz, 2H), 7.58 (d, J=8.3 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.84 (dt, J=7.9, 2.0 Hz, 1H), 8.50 (d, J=1.5 Hz, 1H), 8.59 (dd, J=4.9, 1.6 Hz, 1H). HRMS (ESI) m/z 324.1501 [(M+H)+ Calcd for C22H18N3: 324.1501].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1Br.[Mg].[CH2:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([CH:20]2[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[CH2:16][CH2:15]1)[CH2:12][CH3:13].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:23]1([OH:26])[CH2:22][CH2:21][CH:20]([C@H:17]2[CH2:18][CH2:19][C@H:14]([CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16]2)[CH2:25][CH2:24]1
Reactant: Fc1ccc(F)c(Br)c1
Reactant: CCC[C@H]1CC[C@H](C2CCC(=O)CC2)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](C2CCC(O)(c3cc(F)ccc3F)CC2)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 2,5-difluorobromobenzene (1.33 mmol) in THF (10 ml) is added dropwise to magnesium (1.44 mmol). After the addition is completed, the reaction mixture is stirred at 50° C. for 2 hrs. To the reaction mixture, a solution of 4-(trans-4-propylcyclohexyl)cyclohexanone (1.03 mmol) in THF (10 ml) is added dropwise. After the addition is completed, the reaction mixture is stirred for 2 hrs at 50° C. A saturated aqueous solution of ammonium chloride (10 ml) is added in small portions and the aqueous layer is extracted with ethyl acetate (100 ml) twice. The extract is washed with water, and then dried over anhydrous magnesium sulfate. The titled compound is obtained by evaporation of the solvent under reduced pressure.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH:10]=1)[C:8]#[N:9].S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[Cl:17][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: CC(C)Oc1ccc(CO)cc1C#N
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(CCl)cc1C#N
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 85.6 %

Procedure:
5-(Hydroxymethyl)-2-isopropoxybenzonitrile (5.96 g, 31.2 mmol) was dissolved in toluene (90 mL) and thionyl chloride (13.65 mL, 187 mmol) was added. The reaction mixture was warmed to 75° C. and stirred for 20 min. The reaction mixture was diluted with hexanes and washed with water and saturated aqueous sodium bicarbonate. The hexane solution was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (5.6 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.41 (d, J=6.1 Hz, 6H), 4.52 (s, 2H), 4.66 (septet, J=6.1 Hz, 1H), 6.95 (d, J=8.6 Hz, 1H), 7.51 (dd, J=8.7, 2.4 Hz, 1H), 7.57 (d, J=2.3 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([N:16]1[CH2:21][CH2:20][NH:19][CH:18]([CH2:22][CH3:23])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:9]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=2)[CH:18]([CH2:22][CH3:23])[CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCC1CN(Cc2ccccc2)CCN1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1CN(Cc2ccccc2)CCN1c1nccnc1Cl
Temperature: 100 °C
Reaction time: 96 h
Yield: 70.1 %

Procedure:
A mixture of 2,3-dichloropyrazine (3.9 g, 27 mmol), 1-benzyl-3-ethylpiperazine (4.6 g, 22.5 mmol; from Step 1) and K2CO3 (6.2 g, 45 mmol) in DMF (10 mL) was stirred at 100° C. for 4 days. The solvent from the filtered reaction mixture was evaporated off and the residue was purified by column chromatography on silica using heptane/EtOAc (90:10) as eluent to yield 5.0 g (71%) of the title compound as a light yellow oil. HRMS m/z calcd for C17H21ClN4 (M)+ 316.1455, found 316.1448.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[O:20]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C2C=CC=CC=2)C=CC(OCCOC2C=CC(C[C@H](OC)C(O)=O)=CC=2)=CC=1>>[CH3:18][O:17][CH:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:33][C:30]2[CH:29]=[CH:28][C:27]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:32][CH:31]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: CO[C@@H](Cc1ccc(OCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Product: COC(Cc1ccc(OCCOc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 4-phenoxy-phenol via the same procedure used for the preparation of (2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid (Example 283, Step 3) to produce a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)=[N:11][CH:10]=[C:9]2[CH:27]=[O:28])[CH2:2][CH2:3][CH3:4].[Se](=O)=[O:30].C(OCC)(=O)C.CCCCCC>C(O)(=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]([C:18](=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)=[N:11][CH:10]=[C:9]2[CH:27]=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: O=[Se]=O
Reactant: CCCCOc1cc2c(C=O)cnc(Cc3cccc(OC)c3)c2cc1OC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CCCCOc1cc2c(C=O)cnc(C(=O)c3cccc(OC)c3)c2cc1OC
Temperature: 120 °C
Yield: 62.8 %

Procedure:
To a stirred solution of 6-butoxy-7-methoxy-1-(3-methoxy-benzyl)-isoquinoline-4-carbaldehyde (200 mg, 0.53 mmol) in acetic acid (5 mL) was added selenium dioxide (175 mg, 1.58 mmol). The reaction mixture was heated at 120° C. for 1 h. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 6-butoxy-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carbaldehyde as a yellow solid (131 mg, 63% yield).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:20])=[C:8]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[CH:9]=1.[Br:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CCOCC.CN(C=O)C>[Br:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27]([NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:20])=[C:8]([O:10][C:11]2[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=2)[CH:9]=1)=[O:28]
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Reactant: Cc1nc(Br)c(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: Cc1nc(Br)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)[nH]1
Reaction time: 0.08 h
Yield: 274.8 %

Procedure:
DMF (5 mL) was added to a mixture of 3-{[5-(aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile hydrochloride (0.125 g, 0.379 mmol), 4-bromo-2-methyl-1H-imidazole-5-carboxylic acid (0.093 g, 0.455 mmol) and HATU (0.173 g, 0.455 mmol). The mixture was stirred for 5 min then DIPEA (0.132 ml, 0.758 mmol) was added and the yellow solution was stirred at RT under an atmosphere of nitrogen for 2 h. Saturated aqueous NaHCO3 solution (30 mL) and Et2O (10 mL) was added and the suspension was filtered to give 0.50 g of an insoluble white solid. The filtrate was extracted with ethyl acetate (75 mL) and washed with saturated aqueous Na HCO3 solution (2×50 mL), water (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated. The crude material was purified on silica gel (hexanes/ethyl acetate) to give the title compound (0.075 g, 41%) in ca. 70% purity. The material was purified further by Reverse Phase HPLC (MeCN/H2O+0.1% TFA) to give the title compound (0.043 g, 24%) as a white powder. 1H NMR (400 MHz, DMSO-d6+CD3OD) δ ppm 7.66 (br. s., 1H), 7.54 (d, 1H), 7.16-7.35 (m, 4H), 4.44 (br. s., 2H), 2.25 (s, 3H). LCMS m/z 481.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([CH2:12][C:13](O)=[O:14])#[N:11].CN(C)CCCN=C=NCC.Cl.N1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(OCC)(=O)C.CN(C)C=O>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:13](=[O:14])[CH2:12][C:10]#[N:11]
Reactant: N#CCC(=O)O
Reactant: Nc1ccc(F)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#CCC(=O)Nc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
A mixture of 2-chloro-4-fluoroaniline (3.55 g, 24.3 mmol), cyanoacetic acid (2.48 g, 29.2 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide•hydrochloride (7.01 g, 36.5 mmol), 1H-1,2,3-benzotriazol-1-ol (4.94 g, 36.5 mmol), triethylamine (5.10 mL, 36.5 mmol) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 16 hr. The mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtered through a basic silica gel pad. The solvent was evaporated under reduced pressure, and the obtained residue was washed with hexane and collected by filtration to give the title compound (2.84 g, 54%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:25][CH2:26][CH:27]1[CH2:29][CH2:28]1>>[CH:27]1([CH2:26][NH:25][C:21]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[N:19][C:18]=2[CH3:20])=[O:23])[CH2:29][CH2:28]1
Reactant: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Reactant: NCC1CC1
Product: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)NCC1CC1
Yield: 67 %

Procedure:
As described for example 71d, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.2 mmol) was converted, using aminomethylcyclopropane instead of isopropylamine, to the title compound (53 mg, 67%) which was obtained as a white solid. MS: m/e=399.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(N(CC)C(C)C)(C)C.[C:14]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15].O>ClCCl>[Si:18]([O:4][CH2:3][CH2:2][NH2:1])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCN
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To a stirred solution of 2-amino-ethanol (55 g, 900.46 mmol) in dichloromethane (1000 mL) were added N,N-diisopropylethylamine (220 mL, 1260.64 mmol) and tert-butyl-chloro-dimethyl-silane (135.7 g, 900.46 mmol) at 0° C. followed by stirring for 16 h at room temperature. After completion of the reaction, water (500 mL) was added and the resulting mixture extracted with dichloromethane. The separated organic part was washed with water (2×100 mL) and brine (100 mL) and dried and concentrated to get 2-(tert-butyl-dimethylsilanyloxy)-ethylamine (8c) (157 g, 99.44%) as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[S:8][C:4]=2[CH:3]=1.[CH:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](OC2C=CC=CC=2)=[N:20][C:21]#[N:22])=[CH:14][CH:13]=1>C(#N)C>[C:15]1([O:18][C:19](=[N:1][C:2]2[CH:11]=[CH:10][C:5]3[N:6]=[C:7]([SH:9])[S:8][C:4]=3[CH:3]=2)[NH:20][C:21]#[N:22])[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ccc2nc(S)sc2c1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Product: N#CNC(=Nc1ccc2nc(S)sc2c1)Oc1ccccc1
Yield: 29.6 %

Procedure:
Into a 200 mL round bottomed flask are added 6-amino-1,3-benzothiazole-2-thiol (2.26 g, 12.4 mmol), diphenylcyanocarbonimidate (4.43 g, 18.6 mmol) and acetonitrile (50 mL). The reaction mixture is refluxed under nitrogen atmosphere for 16 hrs. The precipitates are collected by filtration and washed with acetonitrile (15 mL). Recrystalization of the solid from ethanol affords the intermediate of N-cyano-N′-(2-mercapto-benzothiazol-6-yl)carbamimidic acid phenyl ester as white solid (1.2 g, 30%). 1H NMR (DMSO-d6) δ 7.20-7.42 (m, 8H), 7.78 (s, 1H), 10.88 (b, 1H); ESIMS: m/z 324.8 (M−H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][C:22](=[O:25])CC.BrCCO>O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:21][CH2:22][OH:25])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C)=O
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OCCBr
Agent: [K+]
Solvent: O
Product: OCCOc1ccc(Oc2ccccc2)cc1
Temperature: 90 °C
Yield: 62 %

Procedure:
To a solution of 4-Phenoxyphenol (3 g, 16.1 mmol), Potassium carbonate (11.1 g, 80.6 mmol), and 2-Butanone (37.5 mL) was added 2-Bromoethanol (3.14 mL, 44.3 mmol). The resulting mixture was stirred and refluxed at 90° C. overnight under nitrogen. The mixture was poured into 30 mL water solution and extracted with ethyl acetate (EtOAc) (3×10 mL). The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo to obtain the crude mixture, which was purified by of silica gel flash chromatography, using EtOAc/hexane (gradient system), to obtain the product (2.3 g, 62%): 1H NMR (400 MHz, CDCL3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13]Br>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:12][CH2:11][CH2:10][Br:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrCCCCBr
Product: BrCCCCOc1ccc(Br)cc1

Procedure:
The procedure is as for Example 53 using as substrate 4-bromophenol and 1,4-dibromobutane.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].N(OCCC(C)C)=O>C1COCC1>[F:17][C:14]([F:15])([F:16])[O:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]2[CH:2]=[C:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]=[N:5]2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(OC(F)(F)F)cc2)c1N
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2ccc(OC(F)(F)F)cc2)c1
Yield: 86.6 %

Procedure:
A solution of aminopyrazole 115 (1.850 g, 5.87 mmol) and isoamyl nitrite (0.83 mL, 6.18 mmol) in THF (20 mL) was refluxed for 14 h, then further isoamyl nitrite (0.83 mL, 6.18 mmol) was added and the solution was refluxed for 6 h. The solvent was removed under reduced pressure to give a solid, which was recrystallised (EtOH) to give ethyl 1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole-4-carboxylate (116) (1.527 g, 87%) as white flakes: mp 114-116° C.; 1H NMR (CDCl3) δ 8.38 (d, J=0.5 Hz, 1H), 8.10 (s, 1H), 7.74 (d, J=9.1 Hz, 2H), 7.34 (d, J=9.1 Hz, 2H), 4.35 (q, J=7.1 Hz, 2H), 1.38 (t, J=7.1 Hz, 3H). APCI MS m/z 301 [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:21])[C:6]([F:8])([F:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][CH:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)[C:4]=2[O:3]1.[C:22]([NH:24][C:25]([NH2:27])=[NH:26])#[N:23]>C(OCCOCCO)C>[NH2:27][C:25]1[N:24]=[C:22]([NH2:23])[C:18]2[CH2:19][CH:14]([CH2:13][C:12]3[C:4]4[O:3][C:2]([F:21])([F:1])[C:6]([F:8])([F:7])[C:5]=4[CH:9]=[CH:10][CH:11]=3)[CH2:15][CH2:16][C:17]=2[N:26]=1
Reactant: O=C1CCC(Cc2cccc3c2OC(F)(F)C3(F)F)CC1
Reactant: N#CNC(=N)N
Solvent: CCOCCOCCO
Product: Nc1nc(N)c2c(n1)CCC(Cc1cccc3c1OC(F)(F)C3(F)F)C2

Procedure:
This compound is prepared in a manner analogous to that of Example 1, using 3.9 grams (0.013 mole) of 4-(2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmethyl)cyclohexanone and 1.2 grams (0.014 mole) of cyanoguanidine in 2-(2-ethoxyethoxy)ethanol, yielding 2,4-diamino-6-(2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmethyl)-5,6,7,8-tetrahydroquinazoline.