Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13](S(C)=O)=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:20]=3[F:29])[C:7]2=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34]>>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34])=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:20]=3[F:29])[C:7]2=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(CO)CO
Reactant: COc1cc(OC)c(F)c(N2Cc3cnc(S(C)=O)nc3N(C3CCCC3)C2=O)c1
Product: COc1cc(OC)c(F)c(N2Cc3cnc(NC(CO)CO)nc3N(C3CCCC3)C2=O)c1

Procedure:
1-Cyclopentyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-(2-hydroxy-1-hydroxymethyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as in Example 2 using 0.4 g (0.92 mmol) 1-cyclopentyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.25 g (2.76 mmol) serinol. The final product was purified by column chromatography (20:1 dichloromethane/methanol). This gave 0.29 g (68%) of 1-cyclopentyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-(2-hydroxy-1-hydroxymethyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid: mp 194° C.–195° C.; MS (APCI) m/z 462.2, 463.2.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=1.N([O-])=[O:18].[Na+]>S(=O)(=O)(O)O.O>[OH:18][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=N[O-]
Reactant: CC(=O)c1cc(N)cc(S(F)(F)(F)(F)F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Temperature: -5 °C
Reaction time: 0.67 h
Yield: 54.7 %

Procedure:
1-[3-Amino-5-(pentafluorosulfanyl)phenyl]ethanone (O4.050; 3.00 g) was dissolved in 35% aqueous sulfuric acid (25 ml) while heating. The solution was cooled to −5° C. and a solution of sodium nitrite (780 mg) in 15 ml of water was added dropwise within 10 min. After 40 min at −5° C., the cooling bath was removed and the mixture was heated to 100° C. for 2 h. After cooling, the mixture was extracted twice with EA. The combined EA phases were washed with saturated sodium hydrogencarbonate solution, dried, filtered and concentrated. The residue was purified using silica gel (80 g cartridge, n-heptane/MtB ether gradient of 0-100% within 40 min). 1.62 g of the title compound were obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([OH:15])=[C:10]([F:16])[CH:9]=1.[Cl:17][C:18]1[CH:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1.O>CN(C)C(=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([O:15][C:11]2[C:12]([F:14])=[CH:13][C:8]([NH2:7])=[CH:9][C:10]=2[F:16])[CH:21]=[CH:20][N:19]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1cc(F)c(O)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1cc(F)c(Oc2ccnc(Cl)c2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
Potassium tert-butoxide (2.4 g, 22 mmol) was added to a solution of 4-amino-2,6-difluorophenol (2.9 g, 20 mmol) in N,N-dimethyl-acetamide (50 mL) and the mixture was stirred at RT under nitrogen for 0.5 h. A solution of 2,4-dichloro-pyridine (2.9 g, 20 mmol) in N,N-dimethyl-acetamide was added, and the reaction was heated to 100° C. under nitrogen for 10 h. After cooling to RT, the reaction was poured into water (100 mL) and the aqueous solution was extracted with ethyl acetate (3×70 mL). The combined organics were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography to give 4-(2-chloropyridin-4-yloxy)-3,5-difluoroaniline (3.0 g, 59% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.31 (d, J=5.7 Hz, 1H), 7.10 (d, J=2.1 Hz, 1H), 7.01 (dd, J=5.7 Hz, 2.1 Hz, 1H), 6.38 (d, J=10.8 Hz, 2H), 5.86 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18]C)=O)(=[O:11])=[O:10].[Cl:23][C:24]1[N:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=1>>[Cl:23][C:24]1[N:29]=[C:28](/[CH:30]=[C:16](/[C:15]2[CH:14]=[C:13]([NH:12][S:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])(=[O:10])=[O:11])[CH:22]=[CH:21][CH:20]=2)\[OH:18])[CH:27]=[CH:26][N:25]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1
Product: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1cc(F)ccc1F
Yield: 85.3 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 5, Step B using methyl 3-(2,5-difluorophenylsulfonamido)benzoate (20.5 g, 62.7 mmol) and 2-chloro-4-methylpyrimidine (8.8 g, 68.9 mmol) the title compound was obtained (22.6 g, 85.3% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.40-13.50 (br s), 10.95-11.12 (br s), 8.72-8.80 (m), 8.57-8.63 (m), 7.77-7.82 (m), 7.36-7.72 (m), 7.22-7.30 (m), 6.43 (s), 4.52 (s); m/z (ES+): 424 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3](=[CH2:14])[CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].CN(C)C=O.[Br-:20].[Na+]>BrCBr>[Br:20][CH2:2][C:3](=[CH2:14])[CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: [Br-]
Reactant: C=C(CCl)CS(=O)(=O)c1ccccc1
Agent: [Na+]
Solvent: BrCBr
Solvent: CN(C)C=O
Product: C=C(CBr)CS(=O)(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 37250.8 %

Procedure:
A solution of crude (2-chloromethyl-prop-2-ene-1-sulfonyl)-benzene (186 g, assumed 0.80 mmol) in a mixture of dibromomethane (400 ml) and of dimethylformamide (800 ml) was stirred at room temperature during the addition of sodium bromide (82 g, 0.80 mmol). The resulting suspension was stirred at 100° C. for 16 hours, then cooled to room temperature and concentrated in vacuo. The crude material was dissolved in of ethyl acetate (750 ml) and the resulting solution was washed with water (750 ml) and brine (750 ml), dried (anhydrous magnesium sulfate) and concentrated in vacuo. The crude product was recrystallised from isopropyl ether to give (2-bromomethyl-prop-2-ene-1-sulfonyl)-benzene (82 g, 37%). Mass spectrum 276 [M+H]+.
Reaction SMILES: [N:1]1([CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:21]OC(OC)OC>C(O)(=O)C>[N:1]1([CH:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:7]2[CH:12]=[CH:11][C:10]3[NH:13][CH:21]=[N:14][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(OC)OC
Reactant: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1N
Solvent: CC(=O)O
Product: c1ccc(C(c2ccc3[nH]cnc3c2)n2ccnc2)cc1
Yield: 65 %

Procedure:
A mixture of 2.64 parts of 4-[(1H-imidazol-1-yl)phenylmethyl]-1,2-benzenediamine, 50 parts of trimethoxymethane and 1.2 parts of acetic acid was stirred and refluxed for 8 hours. The reaction mixture was evaporated in vacuo. The residue was dissolved in dilute hydrochloric acid. The solution was treated with ammonia and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (90:5:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The solid residue was washed with 2-propanone, yielding 1.8 parts (65%) of 5-[(1H-imidazol-1-yl)phenylmethyl]-1H-benzimidazole; mp. 186.2° C. (compound 111).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)[C:15]([NH:17][C:18]2[S:19][C:20]([CH:23]=O)=[CH:21][N:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:33][O:34][C:35](=[O:45])[CH2:36][C:37](=[O:44])[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)[C:15]([NH:17][C:18]2[S:19][C:20]([CH2:23][N:41]3[CH2:40][CH2:39][N:38]([C:37](=[O:44])[CH2:36][C:35]([O:34][CH3:33])=[O:45])[CH2:43][CH2:42]3)=[CH:21][N:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CC(=O)N1CCNCC1
Reactant: CC1CCC(N(C(=O)Nc2ncc(C=O)s2)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: COC(=O)CC(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCC(C)CC3)C3CCN(C(=O)OC(C)(C)C)CC3)s2)CC1
Yield: 24.7 %

Procedure:
Prepared as described in general procedure (P) using 4-[3-(5-formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-ureido]-piperidine-1-carboxylic acid tert-butyl ester (68 mg, 0.15 mmol), 3-oxo-3-piperazin-1-yl-propionic acid methyl ester hydrochloride (54 mg, 0.19 mmol) and sodium triacetoxy-borohydride (38 mg, 0.18 mmol) to afford 23 mg (25%) of the desired product after purification.
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:26]=[CH:25][C:17]([O:18][CH:19]([CH3:24])[C:20]([O:22]C)=[O:21])=[CH:16][CH:15]=1)[C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:13])[CH:9]=2)[N:4]=1.[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]([C:14]1[CH:26]=[CH:25][C:17]([O:18][CH:19]([CH3:24])[C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1)[C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:13])[CH:9]=2)[N:4]=1
Reactant: COC(=O)C(C)Oc1ccc(N(C)c2cnc3cc(Cl)ccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(Oc1ccc(N(C)c2cnc3cc(Cl)ccc3n2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl 2-{4-[N-methyl-N-(6-chloroquinoxalin-2-yl)amino]phenoxy}propionate (1.0 g; compound no 26, Example 8) was suspended in ethanol (5 ml) and a solution of sodium hydroxide (0.11 g) in water (5 ml) was added over a period of 45 minutes. Further ethanol (6 ml) was added and the mixture was stirred at room temperature for a period of 48 hours. The ethanol was removed by distillation under reduced pressure, the residue was dissolved in water and the aqueous solution was acidified to pH 4 by the addition of aqueous 2 M hydrochloric acid. The precipitate was collected by filtration and dried to give the title compound, mp 204° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH2:16]([C:23]1[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:24]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]([CH:33]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[CH2:30][CH2:31][NH2:32])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(CC)CC>C(Cl)Cl>[CH2:16]([C:23]1[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:24]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]([CH:33]([C:42]1[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=1)[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[CH2:30][CH2:31][NH:32][S:12]([C:7]1[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:14])=[O:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccc2c(Cl)nccc12
Reactant: COc1ccc(C(c2ccc(OC)cc2)N(CCN)CCCOc2ccc(Cl)cc2Cc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(c2ccc(OC)cc2)N(CCCOc2ccc(Cl)cc2Cc2ccccc2)CCNS(=O)(=O)c2cccc3c(Cl)nccc23)cc1
Reaction time: 1 h
Yield: 78.2 %

Procedure:
Powdered 1-chloro-isoquinoline-5-sulfonyl chloride (124 mg, 0.473 mmol) is added to a stirred solution of N1-[3-(2-benzyl-4-chloro-phenoxy)-propyl]-N1-[bis-(4-methoxy-phenyl)-methyl]-ethane-1,2-diamine (258 mg, 0.473 mmol) and NEt3 (0.198 mL, 1.42 mmol) in anhydrous CH2Cl2 (5 mL) at ambient temperature under nitrogen. The resultant mixture is allowed to stir for 1 hour. The mixture is chromatographed on silica gel (gradient 0-4% EtOAc in CH2Cl2) to give 285 mg (0.370 mmol, 78% yield) of the title compound as foam. ESIMS: m/z 768 [(M−H)−, 35C, 35Cl], 770 [(M−H)−, 35Cl, 37Cl], 772 [(M−H)−, 37Cl, 37Cl. Analysis for C42H41Cl2N3O5S: calcd: C, 65.45; H, 5.36; N, 5.45; found: C, 65.43; H, 5.27; N, 5.42.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][S-:12].[Na+].Cl>CS(C)=O.C(OCC)(=O)C>[CH3:11][S:12][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(F)nc1
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CSc1ccc(C(=O)O)cn1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-fluoronicotinic acid (0.995 g, 7.05 mmol) in 14 mL of DMSO was added sodium thiomethoxide (1.24 g, 17.6 mmol). The mixture was heated 80° C. for 1 h, cooled to rt, and treated with concentrated hydrochloric acid (4.5 mL, 0.054 mol). After 15 min, the mixture was diluted with ethyl acetate and concentrated in vacuo to provide 6-(methylthio)nicotinic acid that gave a mass ion (ES+) of 170.1 for [M+H]+.
Reaction SMILES: [C:1](O[K])(C)(C)C.P(=O)(OC=[N+]=[N-])OC.[CH3:15][N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]1[CH:22]=[C:23]([CH:27]=O)[CH:24]=[N:25][CH:26]=1>C1COCC1>[C:27]([C:23]1[CH:24]=[N:25][CH:26]=[C:21]([CH:17]2[CH2:18][CH2:19][CH2:20][N:16]2[CH3:15])[CH:22]=1)#[CH:1]
Reactant: CN1CCC[C@H]1c1cncc(C=O)c1
Reactant: CC(C)(C)O[K]
Agent: CO[PH](=O)OC=[N+]=[N-]
Solvent: C1CCOC1
Product: C#Cc1cncc(C2CCCN2C)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
To a solution of tBuOK in THF (0.08 mL, 0.08 mmol) cooled at −78° C. was added dropwise a solution of methyl diazomethyl phosphonate in THF (0.1 mL, 0.08 mmol). The solution was stirred at −78° C. for 5 min, then a solution of 5-(1-methylpyrrolidin-2-yl)pyridine-3-carbaldehyde (V) (0.0126 g, 0.066 mmol) in THF (1 mL) was added via a double tipped needle. The reaction mixture was stirred at −78° C. for 16 h then allowed to warm to RT over 2 h. After evaporation of the solvent under reduced pressure, the crude material was purified by RPLC (silica gel, 10% EtOAC/hexanes) to afford 0.0061 g (51%) of 3-ethynyl-5-(1-methylpyrrolidin-2-yl)-pyridine (VI) as a clear oil. The data were identical to those described in the literature (Bleicher, L. S.; Cosford, N. P. D.; Herbault, A.; McCallum, J. S.; McDonald, I. A. J. Org. Chem. 1998, 63, 1109).
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH2:9])[CH:7]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][N:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH:9][C:37]([C:36]2[CH:40]=[CH:41][C:33]([N:30]3[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:28][CH2:29]3)=[N:34][CH:35]=2)=[O:38])[CH:7]=1
Reactant: NCc1cnc(-c2ccnc(C(F)(F)F)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)NCc3cnc(-c4ccnc(C(F)(F)F)c4)c(F)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (3-fluoro-2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methanamine 84-2 (53 mg, 0.195 mmol), 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid 46-1 (16 mg, 0.195 mmol), and HATU (81.5 mg, 0.214 mmol) were added N,N-diisopropylethylamine (DIEA, 52 μL, 0.298 mmol) and DMF (1.0 mL). The solution was stirred overnight at room temperature and was subjected to silica gel column chromatography with 1:1 ethyl acetate/hexanes as eluent to give tert-butyl 4-(5-(((3-fluoro-2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methyl)carbamoyl)pyridin-2-yl)piperazine-1-carboxylate 46-2.
Reaction SMILES: [CH2:1](Br)[CH3:2].[Mg].[CH2:5]([N:12]1[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCOCC.C1C=CC=CC=1>[CH2:5]([N:12]1[CH2:13][CH2:14][C:15]([CH2:1][CH3:2])([O:16][CH2:17][CH2:18][OH:19])[CH2:20][CH2:21]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCBr
Reactant: c1ccc(CN2CCC3(CC2)OCCO3)cc1
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCC1(OCCO)CCN(Cc2ccccc2)CC1
Yield: 71.5 %

Procedure:
87.5 g of ethyl bromide dissolved in 100 ml of ether were added dropwise over 30 minutes to 19.2 g of magnesium in 100 ml of ether refluxing in a flask and the resulting solution was cooled. A solution of 46.6 g of 8-benzyl-1,4-dioxa-8-aza-spiro [4,5] decane in 250 ml of benzene was added thereto and the ether was evaporated off. 250 ml. of benzene were added and the mixture was refluxed for 20 hours. The mixture was cooled and hydrolyzed with a saturated aqueous ammonium chloride solution. The benzene phase was decanted and the aqueous phase was extracted with methylene chloride. The methylene chloride phase was washed with water until neutral, dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue was distilled to obtain 37.6 g of 2-(1-benzyl-4-ethyl-4-piperidyloxy)-ethanol as a colorless oil boiling at 152°-156° C at 0.5 mm Hg which was used as is for the next step.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:17](OCC)=O)[C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1>O.C(O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([CH3:17])[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1ccc(Br)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(Cc1ccc(Br)cc1)C(=O)O
Temperature: 200 °C
Yield: 82.2 %

Procedure:
A solution of sodium hydroxide (175 g) in water (800 ml) was added to a solution of diethyl (4-bromophenyl)methylmalonate (150 g) in ethanol (850 ml) and the mixture was heated under reflux for 9 hours. Volatile material was removed by evaporation and the residue was dissolved in a solution of sodium hydroxide (130 g) in water (250 ml). The solution was heated under reflux for 2.5 hours, filtered through a bed of diatomaceous earth and the filtrate was acidified with 6M sulphuric acid. The mixture was extracted with ether (4×500 ml) and the extracts were dried (MgSO4). The solution was concentrated and the residue was heated at 200° C. until evolution of carbon dioxide ceased. The residue was dissolved in 1M sodium hydroxide solution (500 ml) and the solution was acidified with 6M sulphuric acid. The mixture was extracted with ether (4×500 ml) and the extracts were dried (MgSO4). The solvent material was removed by evaporation to give 3-(4-bromophenyl)-2-methylpropionic acid (91 g), m.p. 72-73 ° C.; 1H NMR (d6-DMSO): 1.0 (d, 3H), 2.05-2.15 (m, 2H), 2.85-2.9 (m, 1H), 7.1 (d, 2H), 7.4 (d, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH2:20]([N:22]([CH2:29][CH3:30])[CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[CH3:21]>C(#N)C>[CH2:20]([N:22]([CH2:23][CH:24]1[CH2:28][CH2:27][N:26]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:15])[CH2:25]1)[CH2:29][CH3:30])[CH3:21]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: CCN(CC)CC1CCNC1
Solvent: CC#N
Product: CCN(CC)CC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(CC)c3c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
A mixture of 0.5 g (1.8 mmole) 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 5 ml acetonitrile, 0.27 g (1.8 mole) of 1,8-diazobicyclo[5.4.0]undec-7-ene, and 0.3 g (1.9 mmole) of N,N-diethyl-3-pyrrolidinemethanamine was stirred at room temperature overnight. The formed precipitate was filtered, washed with acetonitrile then ethyl ether until dry to yield 0.45 g (60%) of the title compound, mp 210°-211° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:16])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([CH2:8][Br:16])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1cccnc1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccnc1Br

Procedure:
Synthesized from 2-bromo-3-methylpyridine (5.00 g, 29.1 mmol), NBS (5.69 g, 32.0 mmol) and DBPO (352 mg, 1.46 mmol) in CCl4 according to Method A. Yield: 2.87 g, 11.4 mmol, 39%. This compound was directly used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[C:15]([CH:17]=[C:18](OCC)[NH:19][C:20]#[C:21][CH3:22])#[N:16].C(N)C#C.C(C=C(OCC)OCC)#N>>[C:15]([CH:17]=[C:18]([NH:19][CH2:20][C:21]#[CH:22])[NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[O:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=1)#[N:16]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CC#CNC(=CC#N)OCC
Agent: C#CCN
Agent: CCOC(=CC#N)OCC
Product: C#CCNC(=CC#N)NCCSCc1ccc(CN(C)C)o1

Procedure:
When 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine is reacted with 1-cyano-2-ethoxy-2-propynylaminoethylene [prepared from propargylamine and 1-cyano-2,2-bis(ethoxy)ethylene, which itself is prepared by the procedure described in J. Am. Chem. Soc., 71, 47 (1949)], the title product is produced.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=[O:14].[CH2:15]([S:19][CH2:20][CH2:21][OH:22])[CH2:16][CH2:17][CH3:18].[OH-].[K+]>CS(C)=O>[CH2:15]([S:19][CH2:20][CH2:21][O:22][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=[O:14])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCSCCO
Reactant: O=C1CCCCCN1CCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCSCCOCCCCCN1CCCCCC1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 90.2 %

Procedure:
5.24 g of 1-(5-bromopentyl) azacycloheptane-2-one, 1.34 g of 2-(n-butylthio) ethanol, 2.24 g of powderly potassium hydroxide and 30 ml of dimethylsulfoxide were mixed together, agitated at room temperature for 10 hours, extracted with dichloromethane to obtain an extract. The thus obtained extract was washed with water, dried, freed from the solvent by distillation off at reduced pressure and then finally distilled to obtain 2.84 g of colorless 1-[5-(2-butylthioethyl) oxypentyl] azacycloheptane-2-one having the following appearance, column temperature and analysis:
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]([C:12]2[CH:30]=[CH:29][C:15]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=O)[CH2:22][CH2:21]3)=[CH:14][CH:13]=2)[N:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2.[NH3:31]>>[Cl:2][C:3]1[N:4]([C:12]2[CH:30]=[CH:29][C:15]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][CH:23]([C:26]([NH2:31])=[O:28])[CH2:24][CH2:25]3)=[CH:14][CH:13]=2)[N:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C(O)C1CCN(CCCOc2ccc(-n3nc4ccccc4c3Cl)cc2)CC1
Reactant: N
Agent: Cl
Product: NC(=O)C1CCN(CCCOc2ccc(-n3nc4ccccc4c3Cl)cc2)CC1
Yield: 67.8 %

Procedure:
1-{3-[4-(3-Chloro-indazol-2-yl)-phenoxy]-propyl}-piperidine-4-carboxylic acid hydrochloride (0.1 g, 0.25 mmol) and ammonia (28% in H2O, 3.0 g, 49 mmol) using the procedure of step 3 of the Example 11 to provide the title compound (0.07 g, 70%). 1H NMR (400 MHz, CDCl3) δ 7.71(d, J=8.8 Hz, 1H), 7.59-7.56 (m, 3H), 7.37-7.33 (m, 1H), 7.17-7.14 (m, 2H), 7.04 (d, J=8.8 Hz, 2H), 5.46 (br, 1H), 5.33 (br, 1H), 4.10 (t, J=6 Hz, 2H), 3.01 (br d, J=12 Hz, 1H), 2.54 (t, J=6 Hz, 2H), 2.10-1.73 (m, 9H), LC/MS (APCI) m/z: 97%.