Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11].C(OC1C=C(C2ON=C(C3C=CC=C4C=3C=CN4)N=2)C=CC=1OCC)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH2:19][CH2:20][NH:21]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCOc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1Cl
Agent: CCOc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1OCC
Product: CCCOc1ccc(-c2nc(-c3cccc4c3CCN4)no2)cc1Cl
Yield: 99 %

Procedure:
When the product of Step D was substituted for 5-(3,4-diethoxyphenyl)-3-(1H-indol-4-yl)-1,2,4-oxadiazole in Example 34, Step C, the identical process afforded the title compound in 99% yield. 1H-NMR (CDCl3) 1.09 (tr, 3H, J=7.37 Hz); 1.81-1.94 (m, 2H); 3.51 (tr, 2H, J=8.08 Hz); 3.71 (tr, 2H, J=8.48 Hz); 4.08 (tr, 2H, J=6.47 Hz); 6.92 (d, 1H, J=7.44 Hz); 7.00 (d, 1H, J=8.72 Hz); 7.22 (tr, 1H, J=7.85 Hz); 7.65 (d, 1H, J=7.78 Hz); 8.04 (dd, 1H, J=8.63, 2.11 Hz); 8.21 (d, 1H, J=2.09 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.C1CCCCC=1>C(O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: Nc1ccc(N2CCOCC2)cc1C(=O)O
Yield: 90.8 %

Procedure:
The mixture of 6 g of 2-nitro-5-(morpholin-4-yl)benzoic acid, 15 mL of cyclohexene and 3 g of Pd/C (10%) is heated under reflux conditions in 120 mL of ethanol for 6 hours. The hot reaction mixture is filtered through celite filter. The filtrate is evaporated to obtain 4.8 g of the title compound. m.p.: 242° C.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[S:37])=[CH:31][CH:30]=1>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:36]([NH:35][C:32]4[CH:33]=[CH:34][C:29]([O:28][C:27]([F:26])([F:38])[F:39])=[CH:30][CH:31]=4)=[S:37])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: FC(F)(F)Oc1ccc(N=C=S)cc1
Solvent: CC#N
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=S)Nc5ccc(OC(F)(F)F)cc5)c4c(c23)C1=O
Temperature: 25 °C

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 6 ml of acetonitrile. 97 μl (2 molar equivalents) of 4-(trifluoromethoxy)phenyl isothiocyanate was added and the reaction mixture was maintained at room temperature for 16 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 151 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=91%) which was characterized as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.C[N:15](C)CCCN=C=NCC.ON1C(=O)CCC1=O.N>CN(C)C=O.O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Agent: Cl
Agent: N
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution (20 mL) of 2-chloro-4,5-difluorobenzoic acid (1.0 g) in N,N-dimethylformamide were added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.15 g) and N-hydroxysuccinimide (717 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 28% aqueous ammonia solution (2 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-chloro-4,5-difluorobenzamide as a colorless solid (yield: 760 mg, yield: 76%). To a solution (5 mL) of 2-chloro-4,5-difluorobenzamide (300 mg) in N,N-dimethylformamide was added pyridine (0.253 mL), and oxalyl chloride (0.20 mL) was added dropwise thereto under ice-cooling. The reaction mixture was stirred at room temperature for 30 min, water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a colorless solid (yield: 250 mg).
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](O)=[O:4].Cl.[CH3:35][O:36][NH2:37]>>[OH:1][CH:2]([C:3]([NH:37][O:36][CH3:35])=[O:4])[CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Agent: Cl
Product: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 2-hydroxy-4-phenyl-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with O-methylhydroxylamine hydrochloride. ESI-MS [M+H]+: 472.2
Reaction SMILES: N1CCOCC1.[CH:7](=[O:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19].O.O.O.C([O-])(=O)C.[Na+]>O.C(O)(=O)C.C1CCCCC1>[CH:7]([CH:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:19][CH2:18][C:17]([O:21][CH3:22])=[O:20])=[O:16]
Reactant: C=CC(=O)OC
Reactant: CCCCCCCCC=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCCCC1
Product: CCCCCCCC(C=O)CCC(=O)OC
Temperature: 40 °C
Reaction time: 4 h
Yield: 61.6 %

Procedure:
104.4 g (1.20 mol) of morpholine and 210.0 g of cyclohexane are placed in a one-liter round-bottomed flask with a magnetic stirrer, a water separator, a thermometer and an addition funnel. The mixture is brought to a temperature of 65° C. to 70° C. 142.0 g (0.99 mol) of nonanal are added over four hours. The boiling point (80° C.-84° C. at the start of the addition and then 87° C. toward the end of the operation) is thus rapidly obtained. The water formed during the reaction is recovered in a water separator. The reaction medium is then cooled and the cyclohexane and the excess morpholine are distilled off under reduced pressure (about 4400 Pa), without exceeding 60° C. in the bulk. The mixture is cooled to 40° C. and returned to ambient pressure, and 1.5 g of potassium hydroxide in 20 ml of methanol are added to the 4-non-1(E/Z)-enylmorpholine. The mixture is brought to 50° C. and 85.5 g (0.99 mol) of methyl acrylate are added over one hour. The mixture is stirred for fifteen hours at 50° C., and then a further 43.0 g (0.50 mol) of methyl acrylate are added over one hour thirty minutes. After the end of the addition, the mixture is stirred for a further twelve hours at 60° C. The temperature of the reaction medium is increased to 80° C. An aqueous solution of acetic acid buffered to pH 4 (195.7 g of acetic acid, 71.7 g of sodium acetate trihydrate and 232.6 g of water) are added dropwise over two hours at this temperature. Stirring is continued for a further four hours. The phases are allowed to settle and are separated. The aqueous phase is extracted twice with 150 ml of toluene. The organic phases are combined and are washed three times with 100 ml of water and once with 100 ml of brine. The resulting organic phase is dried over magnesium sulfate. After evaporating off the solvent under reduced pressure (3990 Pa), without exceeding 50° C. in the bulk, 237.0 g of crude oxo ester are obtained, and are blanched under high vacuum (70° C. to 120° C. at 93 Pa) to give 152.1 g of 91.0% methyl 4-formylundecanoate (yield: 0.61 mol; 61%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(NC2CCCCC2)CCCCC1.Cl.[CH2:27]([O:34][C:35](=[O:42])[CH2:36][NH:37][C:38](=[O:41])[CH2:39][NH2:40])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C>C(Cl)(Cl)Cl.C(Cl)Cl.C(OCC)(=O)C.C(Cl)(Cl)Cl>[CH2:27]([O:34][C:35](=[O:42])[CH2:36][NH:37][C:38](=[O:41])[CH2:39][NH:40][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NCC(=O)NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Yield: 85.9 %

Procedure:
In 380 ml of a chloroform/methylene chloride/ethyl acetate (7:5:1 by volume) mixed solvent were dissolved 7.13 g (20 mmol) of t-butyloxycarbonylglycine. dicyclohexylamine and 5.18 g (20 mmol) of glycylglycine benzyl ester hydrochloride obtained in Example 1. To this solution, 50 ml of a chloroform solution containing 4.22 g (20 mmol) of EDAC were added at -5° C. with stirring. The resulting mixture was stirred for 24 hours. The resulting chloroform solution was successively washed twice with a 10% by weight aqueous citric acid solution, then twice with water, then twice with a 4% by weight aqueous sodium hydrogen carbonate solution and finally twice with water. Thereafter, the organic phase was dried over anhydrous sodium sulfate. The solvent was then completely removed in vacuo to obtain a white oily material. This was crystallized from hexane to obtain 6.52 g (yield: 86%) of t-butyloxycarbonyl-glycylglycylglycine benzyl ester as a white solid. This benzyl ester was dispersed, to which 130 ml of 4N HCl/ethyl acetate were added. The mixture was stirred for 4 hours and then the solvent was removed in vacuo to obtain white precipitates. The precipitates were washed well with diethyl ether to obtain 4.63 g (yield: 85%) of glycylglycylglycine benzyl ester hydrochloride as a white solid having the following physical properties:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[O:18]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.[OH-].[Na+].Cl>O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[OH:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(O)c(OCc2ccccc2)c1
Temperature: 100 °C
Yield: 99 %

Procedure:
A 200 mL round bottomed flask is charged with 2-(benzyloxy)-1-methoxy-4-nitrobenzene (10.00 g, 38.6 mmol) and DMSO (30 mL). To the stirred suspension is added NaOH (10 N, 10 mL, 100 mmol), and the mixture is heated to 100° C. for 5 h. The solution is cooled to rt, and immersed in a water ice bath, and water (30 mL) is added to the solution. The pH is adjusted to ˜1 by addition of concentrated HCl (10 mL, 121 mmol). The solution is extracted once with toluene (80 mL). The organic phase is washed successively with water (20 mL) and brine (20 mL), and evaporated to dryness yielding 9.37 g (99%) of the title compound as a yellow solid. LCMS (Standard Method): 2.70 min, 268 (M+Na)+. 1NMR (300 MHz, CDCl3) δ 7.92-7.86 (m, 2H), 7.45-7.41 (m, 5H), 7.00 (d, J=8.8 Hz, 1H), 5.20 (s, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]=2)=[CH:7][C:6]=1[CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:22]=[C:23]([NH2:25])[S:24][CH:2]=3)=[C:6]([CH3:21])[CH:7]=2)=[N:14][CH:15]=1
Reactant: COc1ccc(Oc2cc(C)c(C(=O)CBr)c(C)c2)nc1
Reactant: NC(N)=S
Solvent: CCO
Product: COc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)nc1
Yield: 5.7 %

Procedure:
A mixture of 2-bromo-1-{4-((5-methoxypyridin-2-yl)oxy)-2,6-dimethylphenyl}ethanone (18-3, 1.89 g, 5.40 mmol) and thiourea (0.47 g, 6.18 mmol) in 95% EtOH (20.0 mL) was heated at reflux for 2.0 h. The solution was concentrated and added with water (10 mL) and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and washed with hot water. The solids were filtered and dried under vacuum to give 4-{4-((5-methoxypyridin-2-yl)oxy)-2,6-dimethylphenyl}thiazol-2-amine (18-4, 0.10 g) as yellow solids in 5.7% yield: 1H NMR (500 MHz, CDCl3) δ 7.60 (m, 1 H), 7.30 (m, 1 H), 6.89 (m, 1 H), 6.77 (s, 2 H), 6.25 (s, 1 H), 3.83 (s, 3 H), 2.17 (s, 6 H).
Reaction SMILES: [O:1]1[CH2:29][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]2[O:15][C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=3[C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.[CH:30]([NH2:33])([CH3:32])[CH3:31]>>[OH:1][CH:2]([CH2:29][NH:33][CH:30]([CH3:32])[CH3:31])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([C:14]2[O:15][C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=3[C:18]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1
Reactant: O=S(=O)(c1ccc(OCC2CO2)cc1)c1oc2ccccc2c1-c1ccccc1
Reactant: CC(C)N
Product: CC(C)NCC(O)COc1ccc(S(=O)(=O)c2oc3ccccc3c2-c2ccccc2)cc1

Procedure:
Treatment of 2-[(4-(2,3-epoxypropoxy)phenylsulfonyl]-3-phenylbenzofuran with isopropylamine as described in Example 3 gives the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]([C@@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C@H:15]1[NH:23][C:24](OCC)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)C>O1CCCC1>[NH:7]([C@@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C@H:15]1[NH:23][CH3:24])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Nc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN[C@@H]1Cc2ccccc2[C@H]1Nc1ccccc1

Procedure:
To a stirred suspension of LiAlH4 (1.35 g, 0.035 mol) in dry tetrahydrofuran (25 ml) under nitrogen was added dropwise a solution of (±) trans-1-anilino-2-ethoxycarbonylaminoindane (3.50 g, 0.012 mol) in dry tetrahydrofuran (25 ml). The mixture was heated under reflux for 3.25 h. After cooling in ice, wet diethyl ether was added to quench excess LiAlH4, followed by a minimum amount of water. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo to give a cream coloured solid (2.64 g) which was purified by recrystallisation to give the title compound as a colourless solid, m.p.121°-122° C. (from diethyl ether).
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]=[C:15]2[CH:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[CH:17][N:16]2[CH:24]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][NH:25][C:21]([C:19]1[CH:18]=[CH:17][N:16]2[CH:24]=[C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])[N:14]=[C:15]2[CH:20]=1)=[O:22]
Reactant: NCc1ccccn1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)NCc3ccccn3)cc2n1
Yield: 72 %

Procedure:
As described for Example 11b, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid (96 mg, 0.3 mmol) was converted, using 2-(aminomethyl)pyridine instead of aminomethylcyclopropane, to the title compound (89 mg, 72%) which was obtained as a yellow foam. MS: m/e=410.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([CH3:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:22]O)([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:4]=2[CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([CH3:16])[C:11]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[CH:22]=[C:5]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:4]=2[CH:3]=1
Reactant: CN(C)CCC1(CO)c2ccccc2N(C)c2ccc(Cl)cc21
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CN(C)CCC1=Cc2ccccc2N(C)c2ccc(Cl)cc21
Yield: 82.5 %

Procedure:
A mixture of 5 gm of 2-chloro-9-hydroxymethyl-9-(β-dimethylaminoethyl)-10-methyl-acridane, 150 cc of xylene and 25 gm of phosphoric acid anhydride was refluxed for 3 hours under a nitrogen atmosphere and after cooling, the reaction mixture was poured into a water-ice mixture. The mixture was made alkaline by the addition of 35 cc sodium hydroxide solution and was extracted with ethyl acetate. The organic phase was washed with an aqueous sodium chloride solution, dried over magnesium sulfate, treated with charcoal, filtered and evaporated to dryness to obtain 3.9 gm of raw 8-chloro-5-methyl-10-(β-dimethylaminoethyl)dibenzo (b,f) azepine. The 3.9 gm of raw product were dissolved in 15 cc of methanol and a solution of 1.2 gm of fumaric acid in 45 cc of methanol was added thereto. The methanol was distilled off and replaced with ethyl acetate and the mixture was then refrigerated for 48 hours for crystallization and filtered. The precipitate was washed with ethyl acetate and dried to obtain 2.8 gm, the fumarate of 8-chloro-5-methyl-10-(β-dimethylaminoethyl)-dibenzo (b,f) azepine melting at 150°C, then 164°C. Cooling of the mother liquors gave a second crop of 0.25 g of product.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)[CH:5]=[CH:4][N:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>C1COCC1>[CH:10]1([CH2:9][O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Sn:24]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23])[CH:7]=2)[CH2:12][CH2:11]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1cc(OCC2CC2)ccn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(OCC2CC2)ccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a round bottomed flask 2-bromo-4-cyclopropylmethoxy-pyridine (315 mg, 1.38 mmol) was dissolved in THF (6 mL). The solution was cooled to 0° C. and isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 1.1 mL, 1.45 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min then at room temperature for 1.5 h. Tributyltin chloride (0.42 mL, 1.52 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and concentrated to give 4-cyclopropylmethoxy-2-tributylstannanyl-pyridine as a yellow oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1([F:23])[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[F:23][C:2]1([F:1])[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: COc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)CC2(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CCNCC2(F)F)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (R)-t-butyl 3,3-difluoro-4-(4-methoxyphenyl)piperidine-1-carboxylate (65 mg, 0.2 mmol) in DCM (0.8 mL) was added TFA (0.4 mL, 5.2 mmol) at rt. The mixture was stirred for 2 h, then concentrated to dryness in vacuo to afford crude 3,3-difluoro-4-(4-methoxyphenyl)piperidine trifluoroacetate (67.8 mg, 0.2 mmol, 100% yield), which was used in step G without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=3)[N:9]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:3]=1.[H][H]>C1COCC1.CCO.[Pd]>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=2)[CH:3]=1
Reactant: [H][H]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc([N+](=O)[O-])c3)n2)n1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(N)c3)n2)n1
Yield: 76.7 %

Procedure:
A mixture of 4-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-2-(3-nitro-phenyl)-pyrimidine (example 322) (2.1 g, 4.81 mmol) in THF-EtOH 1:1 (100 mL) and 10% palladium on carbon (1 mol %) was hydrogenated (1 bar hydrogen) at 23° C. for 2 h. The catalyst was filtered off, washed with EtOH and the filtrate was completely evaporated totally to leave a crude product, which was purified by silica gel column chromatography with heptane/EtOAc, followed by trituration with diethyl ether to give the title compound as an off-white solid (1.5 g, 76%). MS (ISP) 407.4 [(M+H)+]; mp 167° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C.[C:24]([O:39][CH3:40])(=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O-])=[O:36]>CCOCC>[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:36])([O:39][CH3:40])=[O:38]
Reactant: COC(=O)CCCCCCCCCCC(=O)[O-]
Reactant: CCOC(=O)CCCOc1ccccc1N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCOc1ccccc1NC(=O)CCCCCCCCCCC(=O)OC
Reaction time: 0.33 h
Yield: 83.1 %

Procedure:
To a stirred, ice-cold solution of 0.89 g (4.0 mM) amine (4) and dried triethylamine (1.2 mL) in dry ether (40 mL) is added dropwise over ca. 4 minutes a solution of acid chloride (7) (1.04 g, 4.6 mM) in 20 mL of dry ether. The resultant mixture is allowed to stir cold for 20 minutes, and then at room temperature overnight. After filtering off the triethylamine hydrochloride, the ether filtrate is concentrated in vacuo and the residue chromatographed on an 82 g silica gel column using 20% ethyl acetate/hexane as eluant to give 1.49 g (85%) of (8) as a waxy solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:11])[NH:9][NH:10][C:4]=2[CH:3]=1.[C:12](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:11])[NH:9][N:10]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:4]=2[CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=c1[nH][nH]c2cc(Cl)ncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1[nH]n(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Temperature: 50 °C
Reaction time: 30 h

Procedure:
Into a 2000-mL 4-necked round-bottom flask was placed 6-chloro-1H-pyrazolo[4,3-c]pyridin-3(2H)-one (Intermediate 1B, Step 2; 100 g, 589.73 mmol), Trt-Cl (328 g, 1.18 mol), potassium carbonate (244 g, 1.77 mol), and DMSO (1200 mL). The resulting solution was stirred for 30 h at 50° C. The reaction mixture was cooled to room temperature, then quenched by the addition of water/ice (4 L). The resulting solution was diluted with EtOAc (12 L). The solid was collected by filtration and washed with MeCN (1.5 L) to give 6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3(2H)-one, which was carried onto the next step without further purification. MS ESI calc'd. for C25H18ClN3O [M+1]+ 412. found 412.