Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.BrCCCCOC1CCNCC1.[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl.CCOCC>[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: BrCCCCOC1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.4 g (1.47 mmol) 4-(4-Brom-butoxy)-piperidine hydrogen chloride and 0.198 ml (1.54 mmol) 4-chloro-benzoylchloride in 5 ml of CH2Cl2 was added 1 ml (5.87 mmol) of N-ethyldiisopropylamine. The reaction-mixture was stirred for 1 h at RT, diluted with Et2O and then washed with 1N HCl and water. The crude product was purified by chromatography on silica gel with EtOAc/hexane 1:1, to yield 459 mg (84%) of clean 4-(4-Bromo-butoxy)-piperidin-1-yl)-(4-chloro-phenyl)-methanone, MS: 374 (M+).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O.[CH2:23]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C:26]1=[O:34])[CH3:24]>>[CH2:23]([N:25]1[C:33]2[C:28](=[CH:29][C:30]([C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:31][CH:32]=2)[CH2:27][C:26]1=[O:34])[CH3:24]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN1C(=O)Cc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCN1C(=O)Cc2cc(C(=O)c3ccccc3)ccc21
Temperature: 100 °C
Yield: 42.8 %

Procedure:
To a mixture of 26.18 g. (186 mmoles) of benzoyl chloride and 32.95 g. of aluminum chloride in 30 ml. of nitrobenzene was gradually added 10.0 g. (62.1 mmoles) of 1-ethyloxindole. The reaction mixture was heated to 100° C. for one hour, cooled and added to 2 l. of ice-water with stirring. The mixture was extracted with methylene chloride (5×200 ml.) and the extracts dried over magnesium sulfate and concentrated in vacuo. The nitrobenzene was distilled from the residue under high vacuum and the residue treated with diethyl ether to induce crystallization. The resulting solids were filtered and recrystallized from methylene chloride petroleum ether, 7.05 g. (42.8% yield), m.p. 134°-136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](Cl)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.BrC1C2N(C(C(NC3C=CN=C(Cl)C=3)=O)=CN=2)N=C(Cl)C=1.[CH3:43][O:44][C:45]1[CH:55]=[CH:54][C:48]([CH2:49][NH:50][CH:51]2[CH2:53][CH2:52]2)=[CH:47][CH:46]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:50]([CH:51]2[CH2:53][CH2:52]2)[CH2:49][C:48]2[CH:54]=[CH:55][C:45]([O:44][CH3:43])=[CH:46][CH:47]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: O=C(Nc1ccnc(Cl)c1)c1cnc2c(Cl)cc(Cl)nn12
Reactant: COc1ccc(CNC2CC2)cc1
Agent: O=C(Nc1ccnc(Cl)c1)c1cnc2c(Br)cc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2cc(Cl)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Temperature: 80 °C
Yield: 89 %

Procedure:
A ˜1:1 mixture 6,8-dichloro-N-(2-chloropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(2-chloropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (3 g, 8.6 mmol), N-(4-methoxybenzyl)cyclopropanamine (8.16 g, 23.82 mmol) and N,N-diisopropylethylamine (3.08 g, 23.82 mmol) was suspended in DMF (100 mL) and heated at 80° C. for 1.5 hrs. The reaction mixture was concentrated and dried under reduced pressure for 16 hrs. The residue was suspended in methanol (75 mL) and an off-white solid was collected via Buchner filtration (2×25 mL methanol rinse) to isolate 6-chloro-N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (10.2 g, 21.1 mmol, 89%) as a tan solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=2.21 minutes. [M+H]=483.06.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][O:6][C:7]1[CH:20]=[C:11]2[N:12]([CH2:16][C:17]([OH:19])=O)[CH2:13][CH2:14][CH2:15][N:10]2[C:9](=[O:21])[N:8]=1.[F:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][O:6][C:7]1[CH:20]=[C:11]2[N:12]([CH2:16][C:17]([N:30]3[CH2:31][CH2:32][CH:27]([F:26])[CH2:28][CH2:29]3)=[O:19])[CH2:13][CH2:14][CH2:15][N:10]2[C:9](=[O:21])[N:8]=1
Reactant: FC1CCNCC1
Reactant: O=C(O)CN1CCCn2c1cc(OCc1ccc(F)c(F)c1)nc2=O
Product: O=C(CN1CCCn2c1cc(OCc1ccc(F)c(F)c1)nc2=O)N1CCC(F)CC1

Procedure:
The title compound was prepared by a procedure similar to that described for E13 starting from 2-(8-((3,4-difluorobenzyl)oxy)-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidin-1-yl)acetic acid and 4-fluoropiperidine.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][C@@H:5]1[CH2:10][C@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][N:6]1C(OC)=O.Br>>[F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][C@@H:5]1[CH2:10][C@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][NH:6]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1Cc1ccc(F)cc1F
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@H](Cc3ccc(F)cc3F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
(2S,4R)-Methyl 2-(2,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate 367 mg, 1.04 mmol) (from example 134, step 3) was dissolved in hydrogen bromide (33% in acetic acid, 8.2 mL, 46.87 mmol) and stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4R)-2-(2,4-difluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (144 mg, 47%). 1H NMR (400 MHz, cd3od) δ 1.43 (q, 1H), 1.67 (dq, 1H), 2.01-2.11 (m, 2H), 2.79-2.96 (m, 4H), 3.14-3.23 (m, 1H), 3.27-3.35 (m, 1H), 5.52 (s, 1H), 6.92-7.01 (m, 2H), 7.28-7.35 (m, 1H). HRMS Calculated for [C15H16F2N2O2+H]+: 295.1258. Found: 295.1259
Reaction SMILES: N#N.[F:3][C:4]([F:14])([F:13])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#N)=[CH:7][CH:6]=1.C(O)=[O:16]>[Ni].[Al]>[F:3][C:4]([F:14])([F:13])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:16])=[CH:7][CH:6]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Reactant: O=CO
Agent: [Ni]
Agent: N#N
Agent: [Al]
Product: O=Cc1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
A Parr hydrogenation bottle was purges with N2 and then charged with 25 g of 4-trifluoromethyl benzonitrile, 250 mL of 75% aqueous formic acid and 3.0 g of powdered nickel/aluminum alloy catalyst (50/50). The reaction mixture was shaken at 80° C. with H2 gas (3 atmospheres pressure) for 16 hours. The reaction mixture was continuously extracted with CH2Cl2 and analyzed via Internal Standard GLC which indicated 87.9% yield of 4-trifluoromethyl benzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[CH2:13][N:12](CC)[N:11]([CH2:16][CH3:17])[CH2:10]2)=[O:7])=[CH:4][CH:3]=1.Cl[O-].[Na+]>>[NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[CH2:10][N:11]([CH2:16][CH3:17])[N:12]=[CH:13]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCN1CC(NC(=O)c2ccc(N)cc2)CN1CC
Agent: [Na+]
Agent: [O-]Cl
Product: CCN1CC(NC(=O)c2ccc(N)cc2)C=N1

Procedure:
In accordance with the procedure of Example 12, 4-amino-N-(1,2-diethyl-4-pyrazolidinyl)benzamide is reacted with sodium hypochlorite and the product is isolated.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[S:12][C:11]([S:13]([NH:16][CH:17]2[CH:23]3[CH2:24][CH2:25][CH:18]2[CH2:19][C:20]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:21]=2[CH2:22]3)(=[O:15])=[O:14])=[CH:10][CH:9]=1.[CH3:32][O:33][CH2:34]Cl.O>C1COCC1>[Cl:7][C:8]1[S:12][C:11]([S:13]([N:16]([CH:17]2[CH:23]3[CH2:24][CH2:25][CH:18]2[CH2:19][C:20]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:21]=2[CH2:22]3)[CH2:32][O:33][CH3:34])(=[O:15])=[O:14])=[CH:10][CH:9]=1
Reactant: N#Cc1ccc2c(c1)CC1CCC(C2)C1NS(=O)(=O)c1ccc(Cl)s1
Reactant: COCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COCN(C1C2CCC1Cc1cc(C#N)ccc1C2)S(=O)(=O)c1ccc(Cl)s1
Reaction time: 0.33 h
Yield: 99.8 %

Procedure:
Potassium t-butoxide (1.0M in THF; 1.33 ml, 1.33 mmol) was added to a solution of 5-chloro-N-(2-cyano-5,6,7,8,9,10-hexahydro-6,9-methanobenzo[a][8]annulen-11-yl)thiophene-2-sulfonamide (Example 176) (350 mg, 0.89 mmol) in THF (10 ml) and stirred for 20 mins. Chloromethyl methyl ether (108 μl, 1.42 mmol) was added and the reaction stirred overnight at RT. More reagents were added as necessary until the reaction was complete by NMR. The reaction mixture was poured into water (25 ml) and extracted with ethyl acetate (2×25 ml). The combined organic layers were washed with brine, dried over MgSO4 and evaporated to give 5-chloro-N-(2-cyano-5,6,7,8,9,10-hexahydro-6,9-methanobenzo[a][8]annulen-11-yl)-N-(methoxymethyl)thiophene-2-sulfonamide (388 mg, quant.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[O:8]1[CH2:11][CH2:10][C:9]1=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:8]1[CH2:11][CH:10]([N:1]2[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]2)[CH2:9]1
Reactant: O=C1CCO1
Reactant: OC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: OC1CCN(C2COC2)CC1
Reaction time: 2 h
Yield: 60.4 %

Procedure:
To a suspension of piperidin-4-ol (364 mg, 3.6 mmol) in DCE (30 mL) was added oxetanone (216 mg, 3.0 mmol). After 2 hours, sodium triacetoxyborohydride (1.02 g, 4.8 mmol) was added in one portion. After 20 hours at ambient temperature, the reaction mixture was loaded directly onto a 20 g SCX-2 cartridge which was washed with methanol, then 2N ammonia in methanol. Concentration of the combined basic fractions in-vacuo followed by flash chromatography of the resultant residue (silica, 10 g column, Si-SPE, 0-10% methanol in dichloromethane) afforded the title compound as a colourless oil (285 mg, 52%). 1H NMR (300 MHz, CDCl3): 4.64-4.63 (m, 4H), 3.77-3.77 (m, 1H), 3.49-3.47 (m, 1H), 2.65-2.55 (m, 2H), 2.04 (t, J=10.5 Hz, 2H), 1.94-1.93 (m, 2H), 1.62-1.61 (m, 2H), 1.47 (d, J=4.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:17])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][NH2:16])=[O:14].[CH3:18][N:19]=[C:20]=[O:21]>C(OCC)C>[CH3:18][NH:19][C:20]([NH:16][NH:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[C:2]([F:17])[F:1])=[O:21]
Reactant: NNC(=O)CCCCCCCCCC=C(F)F
Reactant: CN=C=O
Solvent: CCOCC
Product: CNC(=O)NNC(=O)CCCCCCCCCC=C(F)F
Yield: 81.9 %

Procedure:
A stirred solution of 0.5 gram (0.002 mole) of 12,12-difluoro-11-dodecenoic acid hydrazide and 0.11 gram (0.002 mole) of methyl isocyanate in 30 ml of diethyl ether was heated under reflux for three hours. The reaction mixture was concentrated under reduced pressure yielding 0.5 gram of N-methyl-2-(12,12-difluoro-11-dodecenoyl)hydrazinecarboxamide. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12].[BH4-].[Na+].[Cl-].[NH4+]>CO.O1CCCC1>[CH2:6]1[CH:7]([OH:12])[C:8]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:14])[F:13])[C:4]=2[CH2:5]1
Reactant: O=C1CCc2c1cccc2C(F)(F)F
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: OC1CCc2c1cccc2C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
4-(Trifluoromethyl)indan-1-one (300 mg, 1.50 mmol) was dissolved in methanol (2.5 mL) and tetrahydrofuran (2.5 mL), and sodium borohydride (85 mg, 2.25 mmol) was added thereto at 0° C., and then, the resulting mixture was stirred at room temperature for 2 hours. To the reaction solution, a saturated aqueous solution of ammonium chloride was added, and the organic matter was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=95:5 to 67:33 (v/v)), whereby the objective title compound was obtained as a white solid (291 mg, yield: 96%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:23][CH2:22][C:12]3([C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][C:13]3=[O:21])[C:10]=2[CH:11]=1.[NH:24]1[C:32]2[C:27](=CC=C[CH:31]=2)[C:26]2(COC3C=C4C(=[CH:43][C:33]2=3)CCO4)C1=O.Br.BrCC1C=CC=CN=1.ClCC1C=NC(OC)=NC=1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:23][CH2:22][C:12]3([C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:31][C:32]4[CH:27]=[CH:26][CH:33]=[CH:43][N:24]=4)[C:13]3=[O:21])[C:10]=2[CH:11]=1
Reactant: COCCOc1ccc2c(c1)C1(CO2)C(=O)Nc2ccccc21
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: Br
Agent: BrCc1ccccn1
Agent: COc1ncc(CCl)cn1
Product: COCCOc1ccc2c(c1)C1(CO2)C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 5 and making non-critical variations using 5-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 5-(chloromethyl)-2-methoxypyrimidine, 5-(2-methoxyethoxy)-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (65%): mp 140-142° C.; 1H NMR (300 MHz, CDCl3) δ8.57 (d, J=4.8 Hz, 1H), 7.65 (t, J=7.6 Hz, 1H), 7.25-7.11 (m, 4H), 7.06-6.97 (m, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.68-6.62 (m, 1H), 6.59-6.54 (m, 1H), 6.44-6.38 (m, 1H), 5.09 (ABq, 2H), 4.87 (ABq, 2H), 4.11-4.05 (m, 2H), 3.77-3.68 (m, 2H), 3.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.6, 162.1, 160.7, 155.6, 149.5, 142.1, 137.0, 132.4, 128.8, 123.8, 123.6, 123.5, 122.7, 121.6, 121.1, 109.5, 108.2, 97.3, 80.5, 70.9, 67.6, 59.2, 57.7, 46.1; MS (ES+) m/z 403.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[CH:29][CH:28]=1)(=[O:24])=[O:23])([O-:15])=[O:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=3)[CH2:10]2)=[CH:29][CH:28]=1)(=[O:23])=[O:24])([O-:15])=[O:14]
Reactant: NCc1ccc(CN(Cc2ccccn2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Reactant: O=C1CCc2cccc(O)c2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CNC2CCc3cccc(O)c3C2)cc1)Cc1ccccn1
Yield: 105.3 %

Procedure:
Using General Procedure B: Reaction of 8-hydroxy-2-tetralone (110 mg, 0.68 mmol), N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-1,4-benzenedimethanamine (280 mg, 0.68 mmol) and NaBH(OAc)3 (287 mg, 1.4 mmol) in a mixture of CH2Cl2 (10 mL) and acetic acid (0.2 mL) for 18 hours gave, after work-up, ˜400 mg (quant. yield) of the title compound as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:12][C:11]([NH2:21])=[N:10]1.[C:22](OC(=O)C)(=[O:24])C>C(O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[CH:12][C:11]([NH:21][CH:22]=[O:24])=[N:10]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1
Solvent: O=CO
Product: O=CNc1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1
Reaction time: 0.5 h

Procedure:
0.50 g of 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazol-3-ylamine, obtained in the previous Example, is added in small portions to a mixture of 4 ml of formic acid and 0.5 ml of acetic anhydride, cooled in an ice bath. After stirring for 30 min, the solvents are evaporated off under vacuum and the residue is taken up in isopropyl ether. The white solid obtained is filtered off, washed with isopropyl ether and dried under vacuum to give 0.49 g of the expected formamide.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[O:27]=[C:28]1[N:32]([C@H:33]2[C@H:38]([OH:39])[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]2)[C:31](=[O:47])[CH2:30][S:29]1>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:30]3/[C:31](=[O:47])[N:32]([C@H:33]4[C@H:38]([OH:39])[CH2:37][CH2:36][NH:35][CH2:34]4)[C:28](=[O:27])[S:29]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](N2C(=O)CSC2=O)C1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CNCC[C@H]1O

Procedure:
(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-4-hydroxypiperidin-3-yl]-1,3-thiazolidine-2,4-dione was prepared from [2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 6) and 1,1-dimethylethyl trans-3-(2,4-dioxo-1,3-thiazolidin-3-yl)-4-hydroxypiperidine-1-carboxylate (from Example 270) following General Procedure F.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([N+:15]([O-])=O)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].CO>O>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[NH2:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1cccc(C#Cc2ccccc2)c1
Agent: [Na+]
Agent: [S-2]
Solvent: CO
Solvent: O
Product: Nc1cccc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.8 %

Procedure:
To a 5-liter multi-necked flask fitted with a mechanical stirrer, reflux condenser, and thermometer was charged 215.6 g (0.96 mol) of 3-phenylethynylnitrobenzene obtained as described above, 600.2 g (2.5 mol) of sodium sulfide nonahydrate, 2 liters of methanol, and 500 ml of distilled water. The system is brought to 70° C. for 3 hours at which point the reduction is complete by thin layer chromatography. The reaction mixture is cooled to room temperature and the methanol removed by a rotary evaporator. The concentrate is added to a separatory funnel along with 1 liter of toluene. The toluene layer is separated and washed with distilled water until neutral to pH paper. Concentration of the toluene solution followed by vacuum distillation gave 131 g (0.68 mol, 71% yield) of 3-phenylethynylaniline.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@@H:13]([C:22]([OH:24])=O)[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(NC2CCCCC2)CCCCC1.[C:38]([O:42][C:43](=[O:48])[NH:44][CH2:45][CH2:46][NH2:47])([CH3:41])([CH3:40])[CH3:39].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.C(N(CC)CC)C>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][C@H:13]([NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[C:22]([NH:47][CH2:46][CH2:45][NH:44][C:43]([O:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:48])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCN
Agent: C1CCC(NC2CCCCC2)CC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.50 g (0.96 mmol) of 3-{[(benzyloxy)carbonyl]amino}-N-(tert-butoxycarbonyl)-L-alanine-N-cyclohexylcyclohexanamine (1:1) and 0.154 g (0.96 mmol) of tert-butyl(2-aminoethyl)carbamate are dissolved in 10 ml of dimethylformamide and 0.5 ml of triethylamine. Then, at 0° C. (ice bath), 0.314 g (1.64 mmol) of EDC and 0.043 g (0.32 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried to constant weight under high vacuum.
Reaction SMILES: CCOC([N:6]1[CH2:27][CH2:26][C:9](=[C:10]2[C:20]3[N:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([Cl:25])[CH:13]=[CH:12][C:11]2=3)[CH2:8][CH2:7]1)=O.C[Si](I)(C)C.Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:25][C:14]1[CH:13]=[CH:12][C:11]2[C:10](=[C:9]3[CH2:8][CH2:7][NH:6][CH2:27][CH2:26]3)[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH2:18][CH2:17][C:16]=2[CH:15]=1
Reactant: CCOC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Agent: C[Si](C)(C)I
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Clc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Yield: 17.4 %

Procedure:
To a solution of 9.1 g (0.238 mol) of loratadine in 120 mL of dry chloroform, was added 7.5 mL of trimethylsilyl iodide. Then, the mixture was heated to 55°-60° C. under an argon atmosphere overnight. 30 mL of 0.5N HCl was added and the mixture was stirred for some time more. After basifying with NaOH, the resulting solution was extracted with chloroform (2-3 times). The organic phase was dried over sodium sulfate and the solvent was removed, to yield 12.89 g of a residue that was purified by crystallization in acetonitrile. 5.69 g of the desired product was obtained (yield: 77%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH3:13])[N:11]=[C:10]([C:14]([OH:16])=O)[C:9]=2[CH3:17])[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:26][CH3:27])[CH:21]1[CH2:25][CH2:24][NH:23][CH2:22]1)[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH3:13])[N:11]=[C:10]([C:14]([N:23]3[CH2:24][CH2:25][CH:21]([N:20]([CH2:26][CH3:27])[CH2:18][CH3:19])[CH2:22]3)=[O:16])[C:9]=2[CH3:17])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)nn(C)c1-c1cccc(Br)c1
Reactant: CCN(CC)C1CCNC1
Product: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(Br)c3)c2C)C1
Yield: 94 %

Procedure:
In analogy to the procedure described in example 12D], 5-(3-bromo-phenyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid and 3-(diethylamino)pyrrolidine gave the title compound in 94% yield as white needles. MS: 419.2 (MH+, 1 Br).
Reaction SMILES: Br.[N:2]1[CH2:3][CH2:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[C:6]2[NH2:15].[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:2]1[CH2:3][CH2:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[C:6]2[NH:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1
Reactant: NC1=Nc2ccccc2C2=NCCN12
Reactant: O=C(O)c1cccnc1
Agent: Br
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1=Nc2ccccc2C2=NCCN12)c1cccnc1
Temperature: 80 °C
Yield: 82.6 %

Procedure:
To a suspension of 2,3-dihydroimidazo[1,2-c]quinazolin-5-ylamine hydrobromide (500 mg, 1.87 mmol) and nicotinic acid (346 mg, 2.81 mmol) in N,N -dimethylformamide (25 ml) at room temperature was added benzotriazole-1-yl-oxy-tris-pyrrolidino -phosphonium hexafluorophosphate (1.46 g, 2.81 mmol) followed by N,N-diisopropylethylamine (1.30 ml, 7.49 mmol). The mixture was heated at 80° C. for 4 hours. After cooling to room temperature, the mixture was quenched with aqueous saturated NaHCO3 solution. The resulting precipitate was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give N-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (450 mg, 83% yield).