Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]3[CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1nc2ccc(F)cc2s1
Product: CCOC(=O)c1cn2c(n1)sc1cc(F)ccc12
Yield: 19.1 %

Procedure:
Ethyl 7-fluoro-imidazo[2,1-b]-benzthiazole-2-carboxylate was prepared according to the procedure as outlined in Example 1, (Step 1). Starting from 6-fluoro-2-amino benzothiazole (10.0 g, 59.5 m.mol) and ethyl bromopyruvate (17.4 g, 89.2 mmol), 3.0 g (19% Yield) of ethyl 7-fluoro-imidazo[2,1-b]-benzthiazole-2-carboxylate was isolated as a brown semi-solid. (M+H) 265.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.Cl.Cl[CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:1][C:2]1[N:3]([CH2:19][C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1
Reactant: Cc1cccnc1CCl
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Agent: Cl
Product: Cc1cccnc1Cn1cc(C#Cc2cccc(C#N)c2)nc1C

Procedure:
The title compound, MS: m/e=313.2 (M+H30), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 2-chloromethyl-3-methyl-pyridine hydrochloride.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19](=[CH:27]O)[C:20](=[O:26])[NH:21]2>>[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19](=[CH:27][NH:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:14][CH:13]=1)[C:20](=[O:26])[NH:21]2
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: O=C1Nc2cccc(F)c2C1=CO
Product: O=C1Nc2cccc(F)c2C1=CNc1ccc(OCCN2CCCC2)cc1
Yield: 77.1 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (690 mg, 1.2 equiv.) and 4-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.79 mmol, 1 equiv.) to give the named compound as a yellow solid (790 mg, 77.0%).
Reaction SMILES: C([NH2:3])C.C([NH:6][C:7](=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)SC)#N>>[N:16]1[CH:17]=[CH:18][N:19]=[CH:20][C:15]=1[CH2:14][S:13][CH2:12][CH2:11][NH:10][C:7]([NH2:6])=[NH:3]
Reactant: CCN
Reactant: CSC(=NCCSCc1cnccn1)NC#N
Product: N=C(N)NCCSCc1cnccn1

Procedure:
Anhydrous ethylamine is reacted with N-cyanoN'-[2-(2-pyrazinylmethylthio)ethyl]- S-methylisothiourea by the procedure of Example 4 to give N-cyano-N'-ethyl-N"[2-(2-pyrazinylmethylthio)ethyl]guanidine.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:20]=[CH:19][C:12]([C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[S:21]1[CH2:26][CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[S:21]1[CH2:22][CH:23]=[C:24]([C:2]2[C:3]([O:8][C:9]3[CH:20]=[CH:19][C:12]([C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:25][CH2:26]1
Reactant: CON(C)C(=O)c1ccc(Oc2nccnc2Cl)cc1
Reactant: CC1(C)OB(C2=CCSCC2)OC1(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CON(C)C(=O)c1ccc(Oc2nccnc2C2=CCSCC2)cc1
Temperature: 120 °C

Procedure:
A mixture of 4-(3-chloropyrazin-2-yloxy)-N-methoxy-N-methylbenzamide (1.4 g, 4.77 mmol), 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.132 g, 5.01 mmol), potassium carbonate (1.976 g, 14.30 mmol), and bis(tri-tert-butylphosphine)palladium(0) (0.244 g, 0.477 mmol) in p-dioxane/H2O (10:1, 11 ml) was heated to 120° C. in 4 h, cooled, taken up in H2O, extracted with EtOAc (3×), dried over MgSO4, concentrated and purified by ISCO (50% EtOAc/hexanes) to give the titled compound. MS [M+1]: 358.1.
Reaction SMILES: C([CH:8]([NH:12][C:13]([NH:15][OH:16])=[O:14])[C:9]([O-:11])=[O:10])C1C=CC=CC=1.[H][H]>[Pd].CO>[OH:16][NH:15][C:13](=[O:14])[NH:12][CH2:8][C:9]([OH:11])=[O:10]
Reactant: [H][H]
Reactant: O=C(NO)NC(Cc1ccccc1)C(=O)[O-]
Agent: [Pd]
Solvent: CO
Product: O=C(O)CNC(=O)NO

Procedure:
5 g of palladium on activated charcoal are added to a solution of 22.4 g (0.1 mole) of benzyl-3-hydroxy-ureido-acetate in 300 ml of methanol. Hydrogen is introduced with shaking. After about 20 minutes the hydrogen uptake is finished. The catalyst is filtered off with suction and the filtrate is evaporated in a vacuum. The solid residue of crude 3-hydroxy-ureido-acetic acid is recrystallized from dioxane.
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[C:17]([C:19]4[C:20]5[CH:27]=[CH:26][N:25](COCC[Si](C)(C)C)[C:21]=5[N:22]=[CH:23][N:24]=4)[CH:16]=[N:15]3)[CH2:11]2)[CH2:6][CH2:5]1.[Cl:39][C:40]1[C:45]([C:46](O)=[O:47])=[CH:44][C:43]([C:49]([F:52])([F:51])[F:50])=[N:42][CH:41]=1>>[Cl:39][C:40]1[C:45]([C:46]([N:4]2[CH2:9][CH2:8][CH:7]([N:10]3[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]4[CH:18]=[C:17]([C:19]5[C:20]6[CH:27]=[CH:26][NH:25][C:21]=6[N:22]=[CH:23][N:24]=5)[CH:16]=[N:15]4)[CH2:11]3)[CH2:6][CH2:5]2)=[O:47])=[CH:44][C:43]([C:49]([F:51])([F:50])[F:52])=[N:42][CH:41]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Reactant: O=C(O)c1cc(C(F)(F)F)ncc1Cl
Agent: Cl
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)c3cc(C(F)(F)F)ncc3Cl)CC2)C1

Procedure:
Reaction of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride with 5-chloro-2-trifluoromethylisonicotinoic acid following the procedure described for Example 1, followed by HPLC purification (method B) provided the title compound. LC-MS: 570.2 (M+H)+. 1H NMR (300 MHz, DMSO-d6): δ 12.08 (brs, 1H), 8.92 (, 1H), 8.80 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 8.11 (d, J=14.09 Hz, 1H), 7.59 (d, J=3.30 Hz, 1H), 7.04 (d, J=3.30 Hz, 1H), 4.07 (m, 1H), 3.73 (m, 2H), 3.56 (m, 2H), 3.52 (s, 2H), 3.26 (m, 2H), 2.98 (m, 1H), 2.53 (m, 1H), 1.69 (m, 2H), 1.25 (m, 2H).
Reaction SMILES: O1C2C(=CC=CC=2)/C(=[N:11]/[OH:12])/CC1.[CH2:13]([CH:15]1[C:23](=O)[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[CH2:16]1)[CH3:14]>>[CH2:13]([CH:15]1[CH2:16][C:17]2[C:18](/[C:23]/1=[N:11]\[OH:12])=[N:19][CH:20]=[CH:21][CH:22]=2)[CH3:14]
Reactant: O/N=C1\CCOc2ccccc21
Reactant: CCC1Cc2cccnc2C1=O
Product: CCC1Cc2cccnc2/C1=N\O

Procedure:
Following the procedure for the preparation of (4E)-2,3-dihydro-4H-chromen-4-one oxime but substituting 6-ethyl-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, DMSO-d6) δ) 11.21, 8.45, 7.74, 7.29, 3.27, 3.11, 2.65, 1.84, 1.46, 0.85; HRMS (FAB) calcd for C10H12N2O+H 177.1028, found 177.1029.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:33][CH3:34])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH:25]([CH3:27])[CH3:26])=[C:23]([CH:28]=O)[NH:22][C:21]=1[CH:30]([CH3:32])[CH3:31])=[O:19])[CH3:13]>>[CH2:33]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH:25]([CH3:26])[CH3:27])=[C:23]([CH:28]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:22][C:21]=1[CH:30]([CH3:32])[CH3:31])=[O:19])[CH3:34]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C(C)C)[nH]c(C=O)c1C(C)C
Product: CCN(CC)CCNC(=O)c1c(C(C)C)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1C(C)C
Yield: 62.4 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (100 mg, 0.47 mmol) was condensed with 5-formyl-2,4-diisopropyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (150 mg) to give 0.15 g (62%) of the title compound as a yellow-orange solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Br:12]Br>C(O)(=O)C>[Br:12][C:10]1[CH:11]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: BrBr
Reactant: CC(C)Oc1ccc(N)cc1
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Isopropoxyaniline (24.2 g) was dissolved in acetic acid (300 mL), and a mixture of bromine (8.25 mL) and acetic acid (80 mL) was added dropwise. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure. Water was added to residue, and the mixture was extracted with diethylether. The extract was washed successively with aqueous sodium thiosulfate solution and brine, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 2-bromo-4-isopropoxyaniline (10.2 g) as a black brown oil.
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2[C@H:23]3[C@H:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)[C:17](=[O:24])[NH:16][N:15]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]>>[CH:4]1([O:5][C:6]2[CH:7]=[C:8]([C:14]3[C@H:23]4[C@H:18]([CH2:19][CH:20]=[CH:21][CH2:22]4)[C:17](=[O:24])[NH:16][N:15]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:10][CH2:11][CH2:6][CH2:7]1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: NN
Solvent: O
Product: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)cc1OC1CCCC1

Procedure:
Prepared from compound E (see starting compounds) and hydrazine hydrate as described for compound 1. M.p. 166-168° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][C:7](=[O:13])[C:6]=2[CH:14]=1.I[CH:16]([CH3:18])[CH3:17]>>[CH:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH3:12])[O:8][C:7](=[O:13])[C:6]=2[CH:14]=1)([CH3:18])[CH3:17]
Reactant: CC(C)I
Reactant: CC1(C)OC(=O)c2cc(O)ccc2O1
Product: CC(C)Oc1ccc2c(c1)C(=O)OC(C)(C)O2

Procedure:
The title compound was prepared from 6-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one (example 38-a) and 2-iodopropane under conditions analogous to experimental example 38-b, to give the desired product as a white solid. MS: (+) m/z 237.12 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([CH3:13])([CH3:12])[NH:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[NH2:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]1[CH:3]=[C:2]([NH:1][C:17]2[N:22]=[C:21]([NH:23][C:24]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:25]=3[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=2)[CH:15]=[CH:14][C:5]=1[C:6]([CH3:13])=[CH2:12]
Reactant: CNC(=O)c1cccc(C)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)NC(=O)CCc2cc(N)ccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: C=C(C)c1ccc(Nc2ncc(Cl)c(Nc3c(C)cccc3C(=O)NC)n2)cc1CCC(N)=O

Procedure:
A suspension of 7-amino-1,1-dimethyl-1,2,4,5-tetrahydrobenzo[c]azepin-3-one (46 mg), 2-(2,5-dichloropyrimidin-4-ylamino)-N,3-dimethylbenzamide (42 mg), and camphorsulfonic acid (40 μL of a 100 mg/mL aqueous solution) were heated in isopropanol (2 mL) for 4 hours at 120° C. using microwave irradiation. The solvent was evaporated to afford crude 2-(2-(3-(3-amino-3-oxopropyl)-4-(prop-1-en-2-yl)phenylamino)-5-chloropyrimidin-4-ylamino)-N,3-dimethylbenzamide. The crude mixture was dissolved in TFA and allowed to stand for 4 hours, then concentrated. Purification by semi-preparative HPLC provided 2-(5-chloro-2-(1,1-dimethyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-ylamino)pyrimidin-4-ylamino)-N,3-dimethylbenzamide as the TFA salt. The non-salt was obtained by stirring the TFA salt in acetonitrile with 300 mg of MP-carbonate (Argonaut, 2.91 mmol/g) for 2 days. The resin was separated by filtration, then washed with methanol and methylene chloride. The filtrate was concentrated and the residue triturated with ethyl ether to provide 14 mg of the neutral compound: 1H NMR (300 MHz, CDCl3 with 5% CD3OD) δ 8.05 (s, 1H), 7.5-7.4 (m, 2H), 7.35 (dd, 1H), 7.3 (d, 1H), 7.15 (d, 1H), 7.1 (dd, 1H), 2.9 (s, 3H), 2.8 (m, 2H), 2.6 (m, 2H), 2.3 (s, 3H) 1.8 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][CH2:15]OS(C)(=O)=O)[CH2:12][N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[C:10](=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([S-:31])[CH3:30].[Na+].CCOC(C)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][CH2:15][S:31][CH2:29][CH3:30])[CH2:12][N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[C:10](=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC[S-]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2cccc(Cl)c2)C[C@@H]1CCOS(C)(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCSCC[C@H]1CN(c2cccc(Cl)c2)C(=O)CN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of the mesylate from Step F (3.6 g, 8.3 mmol) in 100 mL of DMF at 0° C. was added sodium ethanethiolate (1.4 g, 16.6 mmol). After 2 hours, the reaction was poured into EtOAc, washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](O)=[O:25])=[CH:19][CH:18]=1>>[C:1]([C:5]1[C:6]([NH:14][C:24](=[O:25])[CH2:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(CC(=O)Nc2nn3cccnc3c2C(C)(C)C)cc1

Procedure:
The product from Example 105B and 4-methoxyphenylacetic acid were processed using the method analogous to that described in Example 137 to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (s, 9H), 3.55 (s, 2H), 3.74 (s, 3H), 6.87-6.97 (m, 2H), 6.99 (dd, J=7.1, 4.1 Hz, 1H), 7.23-7.26 (m, 2H), 8.47 (dd, J=3.9, 1.9 Hz, 1H), 8.91 (dd, J=7.0, 1.5 Hz, 1H), 9.87 (s, 1H); MS (DCI) m/z 339 (M+H)+.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:11]([CH2:19][CH3:20])[C:12](=O)[C:13]([O:15]CC)=[O:14]>C1(C)C=CC=CC=1>[CH2:19]([C:11]1[S:8][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][C:12]=1[C:13]([OH:15])=[O:14])[CH3:20]
Reactant: NC(=S)c1ccccc1
Reactant: CCOC(=O)C(=O)C(Br)CC
Solvent: Cc1ccccc1
Product: CCc1sc(-c2ccccc2)nc1C(=O)O

Procedure:
Intermediate 2C was prepared as described above for the preparation of intermediate 2B from 4.61 g of thiobenzamide, 5.0 g of ethyl 3-bromo-2-oxo-pentanoate, and 14 mL of toluene. Solids were collected and washed with cold water after cooling of the NaOH solution. Heating these solids with citric acid as described followed by cooling and isolation of the resulting solids gave 3.74 g (72% yield) of intermediate 2C; 1H NMR (CDCl3, 300 MHz) δ7913-7.91 (m, 2H), 7.51-7.50 (m, 3H), 3.39 (q, 2H, J=7.8), 1.42 (t, 3H, J=7.8); low resolution MS (ES+)m/e 233.81 (MH+).
Reaction SMILES: [OH:1][C:2]1([CH2:16][C:17](O)=O)[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:20][NH:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]2[CH:33]=[C:32]([CH3:34])[O:31][C:28]2=[N:29][CH:30]=1>>[CH3:20][N:21]([CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]2[CH:33]=[C:32]([CH3:34])[O:31][C:28]2=[N:29][CH:30]=1)[CH2:17][CH2:16][C:2]1([OH:1])[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]2[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CNCCCc1cnc2oc(C)cc2c1
Reactant: O=C(O)CC1(O)CC2CCC1C=C2c1ccccc1
Product: Cc1cc2cc(CCCN(C)CCC3(O)CC4CCC3C=C4c3ccccc3)cnc2o1

Procedure:
Prepared according to procedures P2.2 to P2.3 in Example 21 using rac-(1R*,2R*,4R*)-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)acetic acid and methyl-[3-(2-methyl-furo[2,3-b]pyridin-5-yl)-propyl]-amine.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:21]=[CH:20][C:9]2[CH:10](O)[C:11]3[C:16]([CH2:17][S:18][C:8]=2[CH:7]=1)=[CH:15][CH:14]=[CH:13][N:12]=3.[OH-].[Na+]>C(Cl)Cl>[Cl:5][C:6]1[CH:21]=[CH:20][C:9]2[CH:10]([Cl:3])[C:11]3[C:16]([CH2:17][S:18][C:8]=2[CH:7]=1)=[CH:15][CH:14]=[CH:13][N:12]=3
Reactant: O=S(Cl)Cl
Reactant: OC1c2ccc(Cl)cc2SCc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Clc1ccc2c(c1)SCc1cccnc1C2Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
Add thionyl chloride (3.1 mL, 0.0425 mol) dropwise to a stirred suspension of 8-chloro-5,11-dihydro[1]benzothiepino[4,3-b]pyridin-11-ol (8.8 g, 0.0334 mol) in CH2Cl2 (75 mL) at 3°-8° C. Stir the mixture at room temperature for 3 hours, and pour it into 150 mL of 2.5M NaOH containing ice. Filter, separate the aqueous layer and extract it with CH2Cl2 (2×50 mL). Combine the organic extracts, and wash with water (3×50 mL) and brine (1×75 mL). Dry the mixture over MgSO4, filter, and concentrate in vacuo to obtain the title compound (8.0 g, 80%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[N:12][C:11]([CH3:15])=[N:10]2)[CH:3]=1.[CH2:16]([Sn](CCCC)(CCCC)C=C)[CH2:17]CC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:15][C:11]1[N:12]=[C:13]([CH3:14])[N:9]([C:4]2[CH:3]=[C:2]([CH:16]=[CH2:17])[CH:7]=[C:6]([CH3:8])[N:5]=2)[N:10]=1
Reactant: Cc1cc(Cl)cc(-n2nc(C)nc2C)n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(C)nc(-n2nc(C)nc2C)c1
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methylpyridine (24-3, 456 mg, 2.05 mmol), tributyl(vinyl)tin (845 mg, 2.67 mmol), and tetrakis(triphenylphosphine)-palladium(0) (118 mg, 0.102 mmol) in toluene (10 mL) was refluxed under an atmosphere of argon for 2 hours and cooled to room temperature. The mixture was concentrated and the residue was purified by silica gel column chromatography (0-90% ethyl acetate in hexanes) to give 2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methyl-4-vinylpyridine (25-1) as a light yellow oil. 1H NMR (300 MHz, CDCl3) 57.60 (s, 1H), 7.09 (s, 1H), 6.68 (dd, 1H, J=17.6, 10.9 Hz), 6.03 (d, 1H, J=17.6 Hz), 5.52 (d, 1H, J=10.9 Hz), 2.81 (s, 3H), 2.55 (s, 3H), 2.42 (s, 3H). LRMS m/z (M+H) 215 found, 215 required.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:10]=1[CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[NH:6][C:5]2=[S:15].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(Cl)Cl>[NH:4]1[CH:3]=[CH:2][N:1]=[C:10]1[CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[NH:6][C:5]([N:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)=[S:15]
Reactant: CN1CCNCC1
Reactant: S=C1Nc2ccccc2Cc2nccn21
Solvent: ClCCl
Product: CN1CCN(C(=S)Nc2ccccc2Cc2ncc[nH]2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The mixture of 2.1 g of 11H-imidazo[1,2-c][1,3]benzodiazepine-5(6H)-thione, 23 ml of methylene chloride and 1.0 g of 1-methylpiperazine is stirred at room temperature for 15 hours. The crystalline product formed is filtered off and washed with methylene chloride, to yield 1-[2-(2-imidazolylmethyl)phenylthiocarbamoyl]-4-methylpiperazine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][C:16]1[C:17]([C:26]([F:29])([F:28])[F:27])=[N:18][N:19]([CH2:22][C:23](O)=[O:24])[C:20]=1[CH3:21].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:15][C:16]1[C:17]([C:26]([F:28])([F:27])[F:29])=[N:18][N:19]([CH2:22][C:23]([N:12]2[CH2:11][CH2:10][N:9]([C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:14][CH2:13]2)=[O:24])[C:20]=1[CH3:21]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)c1
Reaction time: 6 h

Procedure:
To 38 mg (0.20 mmol) of 1-(2,5-Dimethylphenyl)piperazine and 53 mg (0.22 mmol) of (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid in 1.6 mL of anhydrous dimethylformamide was added 62 mg (0.6 mmol) of triethylamine, followed by 84 mg (0.22 mmol) of O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU). After 6 hours, the reaction was partitioned between ethyl acetate and water, and the phases were separated. The aqueous phase was back-extracted once with ethyl acetate, and the combined ethyl acetate phases were washed once each with 0.5M pH=7 phosphate buffer, water, 1M NaOH, water, brine. The ethyl acetate phase was then dried over Na2SO4, filtered, and concentrated to a residue in vacuo. The residue was dissolved in a minimum volume of 5M HCl in isopropanol, and was precipitated by diluting the solution with ethyl acetate. The product was isolated by filtration to give a white solid: 1H NMR (DMSO-d6, 400 MHz) 7.07 (d 1H), 6.90 (s, 1H), 6.82 (d, 1H), 5.39 (s, 2H), 3.66 (m, 4H), 2.98 (m, 2H), 2.89 (m, 2H), 2.26 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H) ppm; MS (ES) M+H expected=415.1, found 415.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20](B4OC(C)(C)C(C)(C)O4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:35][N:34]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20]([C:33]4[CH:38]=[CH:37][C:36]([CH2:39][S:40]([CH3:43])(=[O:41])=[O:42])=[CH:35][N:34]=4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3O2)CC1
Reactant: CS(=O)(=O)Cc1ccc(Cl)nc1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(CS(C)(=O)=O)cn4)ccc3O2)CC1

Procedure:
The title compound is prepared from 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid tert-butyl ester and 2-chloro-5-methanesulfonylmethyl-pyridine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.17 min; Mass spectrum (ESI+): m/z=473 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1)=[CH:5][NH:6]2.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:11]1[CH2:12][CH2:13][N:14]([CH2:19][C@H:18]([OH:17])[CH2:20][O:21][C:22]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:23]=3[CH:24]=[CH:25][NH:26]4)[CH2:15][CH:16]=1)=[CH:5][NH:6]2
Reactant: Fc1cccc2[nH]cc(C3=CCNCC3)c12
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2c[nH]c3cccc(F)c23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 4-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.50 g, 2.3 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.44 g, 2.3 mmol). The resulting free base was obtained as a yellow foam. Yield 0.14 g (15%). mp 90°-95° C. FDMS m/e=405 (M+ of free base).