Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([OH:27])=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][C:11]([CH3:28])=[C:10]([CH3:29])[N:9]=2)[S:5][C:6]=1[CH3:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][OH:39]>CN(C)C=O>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH2:37][CH2:38][OH:39])=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][C:11]([CH3:28])=[C:10]([CH3:29])[N:9]=2)[S:5][C:6]=1[CH3:7]
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3nc(C)c(C)s3)ccnc2cc1O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3nc(C)c(C)s3)ccnc2cc1OCCO
Temperature: 70 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
4-[2-(4,5-Dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-yloxy]-6-methoxy-quinolin-7-ol (compound 455) (41 mg) was suspended in N,N-dimethylformamide (2 ml). Potassium carbonate (42 mg) and 2-bromoethanol (0.02 ml) were added to the suspension, and the mixture was stirred at 70° C. overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (47 mg, yield 100%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]([C:23]1[C:28]([C:29]2[O:30][C:31]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][NH:41][CH3:42])=[CH:36][C:35]=3[O:43][CH3:44])=[N:32][N:33]=2)=[N:27][C:26]([C:45]2[CH:50]=[CH:49][C:48]([S:51]([CH:54]([CH3:56])[CH3:55])(=[O:53])=[O:52])=[CH:47][CH:46]=2)=[CH:25][N:24]=1)C(=O)OC(C)(C)C)=O)(C)(C)C>C(Cl)Cl>[CH:54]([S:51]([C:48]1[CH:47]=[CH:46][C:45]([C:26]2[N:27]=[C:28]([C:29]3[O:30][C:31]([C:34]4[CH:39]=[CH:38][C:37]([CH2:40][NH:41][CH3:42])=[CH:36][C:35]=4[O:43][CH3:44])=[N:32][N:33]=3)[C:23]([NH2:15])=[N:24][CH:25]=2)=[CH:50][CH:49]=1)(=[O:53])=[O:52])([CH3:56])[CH3:55]
Reactant: CNCc1ccc(-c2nnc(-c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1ccc(-c2nnc(-c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc3N)o2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
TFA (393.7 mg, 266.0 μL, 3.453 mmol) was added to a solution of tert-butyl N-tert-butoxycarbonyl-N-[5-(4-isopropylsulfonylphenyl)-3-[5-[2-methoxy-4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]carbamate (80 mg, 0.1151 mmol) CH2Cl2 (10 mL). The resulting mixture was stirred at room temperature for 1 h, and then concentrated in vacuo to leave an oil. The oil was re-dissolved in CH2Cl2 (10 ml), and evaporated to dryness. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3 CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as a yellow solid (27.1 mg, 39%); 1H NMR (400 MHz, DMSO) d 1.3 (d, 6H), 2.65-2.7 (m, 3H), 3.4-3.5 (m, 1H), 4.0 (s, 3H), 4.25-4.3 (m, 2H), 7.25 (d, 1H), 7.5 (s, 1H), 8.0 (d, 2H), 8.1 (d, 1H), 8.38 (d, 2H), 8.92 (br s, 2H) and 9.1 (s, 1H) ppm; MS (ES+) 495.3
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([C:27]#[N:28])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([C:29]([F:32])([F:31])[F:30])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:33]([NH2:36])([CH3:35])[CH3:34]>C(#N)C.O>[CH:33]([NH:36][C:21]([C:20]1[C:15]([NH:14][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([C:29]([F:30])([F:31])[F:32])[CH:11]=2)=[O:22])=[C:16]([C:27]#[N:28])[CH:17]=[C:18]2[C:19]=1[NH:24][N:25]=[CH:26]2)=[O:23])([CH3:35])[CH3:34]
Reactant: CC(C)N
Reactant: N#Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: O
Solvent: CC#N
Product: CC(C)NC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)c(C#N)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 600 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-9-oxo-1,9-dihydro-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalene-5-carbonitrile in 5 mL of acetonitrile/water (4:1, v/v) is added 1.1 mL (12.9 mmol) of isopropylamine. The reaction mixture is stirred during 4 hours at ambient temperature and then concentrated in vacuo. After purification by flash chromatography (SiO2, hexanes/ethyl acetate 4:1), 250 mg (38%) of a white solid are obtained; LC/MS:518/520 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[CH:19]=[N:18][N:17]=[N:16]1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([N:15]3[CH:19]=[N:18][N:17]=[N:16]3)=[CH:21][CH:22]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(O)c1ccc(-n2cnnn2)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(-n2cnnn2)cc1

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 4-(1H-tetrazol-1-yl)benzoic acid to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(1H-tetrazol-1-yl)benzamide. MS (Q1) 421.0 (M)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH:10]([CH3:14])[C:11]([OH:13])=O)=[C:4]([O:15][CH3:16])[CH:3]=1.[N:17]1([CH:23]2[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH:10]([CH3:14])[C:11]([N:20]2[CH2:21][CH2:22][N:17]([CH:23]3[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]3)[CH2:18][CH2:19]2)=[O:13])=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: COc1cc(Cl)c(I)cc1NC(C)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(N2CCNCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(I)cc1NC(C)C(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
To a solution of 2-(4-chloro-5-iodo-2-methoxyphenylamino)propanoic acid (760 mg, 2.13 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (669 mg, 2.78 mmol), EDCI.HCl (818 mg, 4.26 mmol), HOBt (575 mg, 4.26 mmol) in DMF (8 mL) at 0° C., Et3N (861 mg, 8.52 mmol) was added. The resulting mixture was stirred at RT for 16 h and then partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether=1:1) to afford the desired product (673 mg, 55% yield) as a white solid. ESI-MS m/z: 579.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[N:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[CH:19]([O:22][C:23]1[NH:27][N:26]=[C:25]([NH2:28])[CH:24]=1)([CH3:21])[CH3:20]>C(#N)C.O>[F:1][C:2]1[N:9]=[C:8]([NH:28][C:25]2[CH:24]=[C:23]([O:22][CH:19]([CH3:21])[CH3:20])[NH:27][N:26]=2)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(F)c(F)nc1F
Reactant: CC(C)Oc1cc(N)n[nH]1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)Oc1cc(Nc2nc(F)c(C#N)cc2F)n[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
To a solution of 2,5,6-trifluoronicotinonitrile (3.0 g, 19.0 mmol) and triethylamine (2.5 g, 24.7 mmol) in ACN (30 ml) at 0° C. was added 5-isopropoxy-1H-pyrazol-3-amine (2.95 g, 20.9 mmol) in ACN (15 ml). The reaction was stirred at 0° C. for 1 hour, at which point the reaction was diluted with water (50 ml) and extracted with DCM (2×50 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (0.48 g, 9%). MS: Calcd.: 279. Found: [M+H]+ 280.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][F:1])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCCF
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCCF)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.7 %

Procedure:
2-(2-Fluoroethoxy)ethanol (0.11 g, 1.0 mmol), p-toluenesulfonyl chloride (0.19 g, 1.0 mmol), and DMAP (0.12 g, 1.0 mmol) were dissolved in dichloromethane (2 ml) at 0° C. The resulting mixture was stirred for 2 h at 0° C., after which it was subjected directly to silica gel chromatography using dichloromethane as the eluent to give the title compound (70 mg, 27%) as a clear oil. It was observed that the size of the column affects reaction yield, with a smaller column giving a better yield. 1H NMR (CDCl3, 300 MHz): δ 7.79 (d, 2H, J=11.6 Hz), 7.33 (d, 2H, J=11.6 Hz), 4.48 (dt, 2H, J1=64.0 Hz, J2=5.6 Hz), 4.17 (t, 2H, J=6.4 Hz), 3.71 (t, 2H, J=6.4 Hz), 3.66 (dt, 2H, J1=5.6 Hz, J2=39.2 Hz), 2.44 (br S, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:13])[CH2:6][CH2:5]2.[CH3:19][I:20]>CC#N>[I-:20].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([N:14]1[CH:18]=[CH:17][N+:16]([CH3:19])=[CH:15]1)=[O:13])[CH2:6][CH2:5]2
Reactant: CI
Reactant: O=C(N1CCc2cc(Br)ccc2C1)n1ccnc1
Solvent: CC#N
Product: C[n+]1ccn(C(=O)N2CCc3cc(Br)ccc3C2)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of compound 1i (1.03 g, 3.37 mmol) in CH3CN (7 mL) was added MeI (0.84 mL, 13.46 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and the residue was washed with Et2O/hexanes to afford compound 1j (1.48 g). 1H NMR (300 MHz, CDCl3): δ 10.44 (s, br, 1H), 7.65 (s, 1H), 7.31 (m, 3H), 7.23 (m, 1H), 5.02 (m, 2H), 4.31 (s, 3H), 3.98 (m, 2H), 3.04 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:28])[C:12]3[S:19][CH:18]=[C:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.C([Li])CCC.C1C[O:54][CH2:53]C1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:28])[C:12]3[S:19][C:18]([CH:53]=[O:54])=[C:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:29][CH:30]=1
Reactant: C1CCOC1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2scc(COCC[Si](C)(C)C)c21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(C=O)c(COCC[Si](C)(C)C)c21
Temperature: -78 °C

Procedure:
To a cold (−78° C.), stirred mixture of 2.03 g of N-(4-chlorobenzyl)-4-methyl-7-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide in 50 mL of dry TBF is added via cannula a solution of LDA, prepared as usual in 25 mL of dry THF from 2.5 mL of diisopropylamine and 5.3 mL of a 2.5 M solution of butyllithium in hexanes. The resulting deeply colored solution is stirred for 5 min at −78° C., then 1.7 mL of dry DMF is added, causing the mixture to solidify. The mixture is allowed to warm to 0° C. whereupon it becomes fluid, and is quenched with 50 mL of 1N HCl. Aqueous workup (CH2Cl2, dil. HCl) followed by flash chromatography on silica gel using 30-40% EtOAc in CH2Cl2 affords 1.56 g of the title compound as a yellow solid. Recrystallization from EtOAc provides pale yellow crystals.
Reaction SMILES: [C@H:1]1([NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[NH2:7].O=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[NH2:7][C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@@H:1]1[NH:8][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: N[C@H]1CCCC[C@@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N[C@H]2CCCC[C@@H]2N)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.1 %

Procedure:
To a solution of (1S,2S)-cyclohexane-1,2-diamine (4 g, 35.08 mmol) in dichloromethane (80 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (3.49 g, 17.54 mmol) followed by sodium triacetoxy borohydride (11.15 g, 52.60 mmol) and stirred at room temperature for 5 hours. A saturated solution of sodium hydrogen carbonate (10 mL) was then added and the reaction diluted in dichloromethane (100 mL). The phases were separated and aqueous phase was extracted with dichloromethane (2×60 mL). Combined organic layers was washed with brine, dried and concentrated in vacuo. The crude compound was purified by flash chromatography to provide the titled compound as yellow oil (3.5 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:18])[N:11]([CH3:17])[C:12](SC)=[N:13][CH:14]=1.[CH2:19]([NH2:22])[CH2:20][CH3:21]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:18])[N:11]([CH3:17])[C:12]([NH:22][CH2:19][CH2:20][CH3:21])=[N:13][CH:14]=1
Reactant: CSc1ncc(-c2ccc(C)cc2C)c(=O)n1C
Reactant: CCCN
Product: CCCNc1ncc(-c2ccc(C)cc2C)c(=O)n1C
Temperature: 100 °C
Yield: 64.7 %

Procedure:
To a sealed tube was added 0.15 g (0.57 mmol) of 5-(2,4-dimethyl-phenyl)-3-methyl-2-(methylthio)pyrimidin-4(3H)-one and 3 ml (50 mmol) of propyl amine. The mixture was heated to 100° C. for 48 h. The reaction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 50% ethyl acetate/hexanes gave 0.1 g (67%) of product.
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[CH:7]=[C:8]([CH:10]=[C:11]([CH:13]([F:15])[F:14])[CH:12]=1)[NH2:9].Cl[C:17]1[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=1>O1CCOCC1.C(OCC)(=O)C>[Br:5][C:6]1[CH:7]=[C:8]([NH:9][C:17]2[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=2)[CH:10]=[C:11]([CH:13]([F:14])[F:15])[CH:12]=1
Reactant: Nc1cc(Br)cc(C(F)F)c1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: FC(F)c1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Temperature: 105 °C
Yield: 34.3 %

Procedure:
Acetic acid (1.01 mL, 17.6 mmol) was added to a mixture of 3-bromo-5-(difluoromethyl)aniline (1.30 g, 5.86 mmol) and 2-chloro-4-(trifluoromethyl)pyrimidine (2.14 g, 11.7 mmol) in dioxane (5.0 mL). The mixture was heated to 105° C. for 16 hrs then cooled to room temperature. The mixture was diluted with ethyl acetate, washed with dilute aqueous NaHCO3, brine and dried. The residue was purified by chromatography on silica gel (0-15% ethyl acetate in hexanes) to yield N-[3-bromo-5-(difluoromethyl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (741 mg, 2.01 mmol, 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[F:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:18]([CH:21]=1)[C:19]#[N:20].C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:25]3[CH2:24][CH2:23][N:22]([C:17]4[CH:16]=[CH:15][C:14]([F:13])=[CH:21][C:18]=4[C:19]#[N:20])[CH2:27][CH2:26]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: N#Cc1cc(F)ccc1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: OCCO
Product: N#Cc1cc(F)ccc1N1CCN(Cc2cn3cc(Cl)ccc3n2)CC1
Yield: 59.6 %

Procedure:
Following the general procedure of Example 11 and making noncritical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1; 0.199 g), 5-fluoro-2-(piperazin-1-yl)benzonitrile (0.203 g), triethylamine (0.110 g), and ethylene glycol (2 mL) give 0.218 g of the title compound after chromatography (silica gel, methanol/dichloromethane, 4/96) and crystallization from dichloromethane/hexane; mp 179-180° C.; MS m/z 369; IR (mineral oil) 1494, 1329, 808, 1452, 1072 cm-1. 1H NMR (CDCl3) δ2.78, 3.20, 3.78, 6.99, 7.13, 7.19, 7.26, 7.51, 7.52.8.14.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10]C)=O.[H-].[Na+].F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.[CH3:23][NH:24][CH2:25][CH2:26][OH:27]>CN(C)C=O.O>[CH3:23][N:24]([CH2:25][CH2:26][O:27][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1)[C:8](=[O:10])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: COC(=O)Cc1ccccn1
Reactant: CNCCO
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCOc1ccc(C=O)cc1)C(=O)Cc1ccccn1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Methyl 2-pyridylacetate (10.0 g, 8.9 ml) was dissolved in 2-(N-methylamino)ethanol (150 ml) and the mixture heated at reflux for 84 hours, then cooled and concentrated under reduced pressure. The residue was dissolved in water (100 ml)and continuously extracted overnight with ethyl acetate. The ethyl acetate solution was dried (MgSO4) and evaporated to afford an oil which no longer displayed an ester signal (δ3.70) in the nmr spectrum. The oil was dissolved in dry dimethylformamide (150 ml) at room temperature under a nitrogen atmosphere, and sodium hydride (60% dispersion in oil, 3.42 g) was added. The mixture was stirred for 1 hour, then 4-fluorobenzaldehyde (10.6 g, 9.2 ml) was added and the mixture heated at 80° C. for 22.5 hours, cooled, diluted with water (1 l) and extracted with ethyl acetate (3×400 ml). The combined ethyl acetate layers were washed with water (3×1 l) and brine (1 l), dried (MgSO4) and evaporated. The resulting oil was triturated with hexane and the residue chromatographed on silica gel with 1.5% methanol in dichloromethane as solvent to afford the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[C:9]([Br:10])=[CH:8][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:16][OH:17].C(=O)(O)[O-].[Na+]>C(O)C.O.O1CCCC1>[OH:1][C:2]1[C:9]([Br:10])=[CH:8][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][C:3]=1[CH:4]=[N:16][OH:17]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(Br)c(O)c(C=NO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A mixture of 12.86 g (50.0 mmol) of 2-hydroxy-3-bromo-5-(1,1-dimethylethyl)benzaldehyde and 3.82 g (55.0 mmol) of hydroxylamine hydrochloride in 30 ml of ethanol, 30 ml of water and 30 ml of tetrahydrofuran was cooled in an ice-water bath. Sodium bicarbonate (5.04 g, 60.0 mmol) was added in small portions over 15 minutes. After stirring for 1 hour at ambient temperature, water (200 mmol) was added and the solid was filtered and dried. There was obtained 13.2 g (48.5 mmol, 97%) of 2-hydroxy-3-bromo-5-(1,1-dimethylethyl)benzaldehyde oxime as a white solid; mp 167°-169° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[CH:17]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:22](=[O:23])[C:21]2[CH:20]=[CH:19][C:18]([N:16]3[CH:17]=[C:13]([C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[CH:15]3)=[CH:26][CH:25]=2)[CH2:29][CH2:28]1
Reactant: NC1CC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)NC3CC3)cc2)cn1
Yield: 12 %

Procedure:
As described for Example 71c, 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) was converted, using cyclopropylamine instead of cyclopropylmethylamine, to the title compound (14 mg, 12%) which was obtained as an off-white solid. MS: m/e=384.9 [M+H]+.
Reaction SMILES: COS([O:6][CH3:7])(=O)=O.[C-]#N.[Na+].C(C1C=CC=CN=1)#N.[NH:19]1[C:29]2[C:23](C=[CH:25][CH:26]=[C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]3=2)=[CH:22][CH:21]=[CH:20]1>>[O:6]=[C:7]1[C:23]2[CH:22]=[CH:21][CH:20]=[N:19][C:29]=2[C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[CH:26]=[CH:25]1
Reactant: COS(=O)(=O)OC
Reactant: C1=CNC2=c3ccccc3=CC=CC2=C1
Agent: [C-]#N
Agent: [Na+]
Solvent: N#Cc1ccccn1
Product: O=c1ccc2ccccc2c2ncccc12

Procedure:
In a process described in U.S. Pat. No. 3,326,924, 3-(2-phenethyl)-2-cyanopyridine is prepared by reacting 3-(2-phenethyl)pyridine-1-oxide with dimethylsulfate and then with aqueous sodium cyanide. A process to convert the cyanopyridine to an aza-dibenzocycloheptene by cyclizing to give the 5-keto-aza-dibenzocycloheptene, then reacting with a Grignard reagent. e.g., 1-methyl-4-piperidinyl magnesium chloride, to give a 5-(1-methyl-4-piperidinyl)aza-dibenzocycloheptene-5-ol, which is dehydrated to give the exocyclic 5-(1-methylpiperidylidenyl) compound, e.g., azatadine, is also described in U.S. Pat. No. 3,326,924.
Reaction SMILES: [Cl:1]Cl.[OH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:15])[CH3:14].[C:16]([OH:19])(=O)[CH3:17]>>[C:13]([NH:12][C:7]1[CH:8]=[CH:9][C:10]([Cl:1])=[CH:11][C:6]=1[CH2:5][CH2:4][O:3][C:16](=[O:19])[CH3:17])(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1ccccc1CCO
Reactant: ClCl
Reactant: CC(=O)O
Product: CC(=O)Nc1ccc(Cl)cc1CCOC(C)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of chlorine in glacial acetic acid (0.98M, 30 ml) was added dropwise to a solution of N-[2-(2-Hydroxy-ethyl)-phenyl]-acetamide (5.0 g, 27.9 mmol)(see reference Biochemistry 1979, 18(5), 860) in glacial acetic acid (50 ml) and the mixture was stirred at room temperature for 20 hours. The glacial acetic acid was removed under reduced pressure. The resulting oil was triturated with diethyl ether to give the title compound (3.3 g) as a pale yellow solid after filtration.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:29][CH2:30][C:31]([O:33]C)=[O:32])([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[CH2:3]1.ClC1C=CC(OCCCOC2C=CC3C(=O)CC(CCC(OCC)=O)(CCC(OCC)=O)OC=3C=2CCC)=CC=1.C(Cl)Cl>C(OCC)(=O)C>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:3]1
Reactant: CCCc1c(OCc2ccccc2)ccc2c1OC(CCC(=O)OC)(CCC(=O)OC)CC2=O
Agent: CCCc1c(OCCCOc2ccc(Cl)cc2)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1c(OCc2ccccc2)ccc2c1OC(CCC(=O)O)(CCC(=O)O)CC2=O

Procedure:
The title compound, 102 mg, m.p. 202°-205° C., was prepared by the method of Example 22 substituting the title product of Example 18 (455 mg) for the title product of Example 21, and utilizing methylene chloride as the extraction solvent instead of ethyl acetate.