Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:17]1[C:22]([O:23][CH2:24][CH3:25])=[CH:21][C:20](=[O:26])[N:19]([CH3:27])[CH:18]=1.[H-].[Na+].Br[CH2:36][CH:37]1[CH2:39][CH2:38]1.O>CN(C=O)C>[CH:37]1([CH2:36][N:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C:3]3[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:2]=3[F:1])=[C:6]([C:17]3[C:22]([O:23][CH2:24][CH3:25])=[CH:21][C:20](=[O:26])[N:19]([CH3:27])[CH:18]=3)[CH:7]=2)[S:12]([CH2:15][CH3:16])(=[O:13])=[O:14])[CH2:39][CH2:38]1
Reactant: BrCC1CC1
Reactant: CCOc1cc(=O)n(C)cc1-c1cc(NS(=O)(=O)CC)ccc1Oc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(=O)n(C)cc1-c1cc(N(CC2CC2)S(=O)(=O)CC)ccc1Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.9 %

Procedure:
To a solution of Example 72A (50 mg, 0.108 mmol) in DMF (1 mL) was added NaH (7.7 mg, 0.32 mmol) and the mixture was stirred at room temperature for 30 minutes. Then (bromomethyl)cyclopropane (43.6 mg, 0.323 mmol) was added and the mixture was stirred at 50° C. for 18 hours. Water (10 mL) was added and the mixture extracted with ethyl acetate (3×15 mL). The combined organics were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by HPLC (C18, CH3CN/water (0.1% NH4HCO3), 40-60%) to provide the title compound (5 mg, 8.96% yield). 1H NMR (400 MHz, CD3OD) δ 7.46 (s, 1H), 7.28 (dd, J=6.9, 2.6 Hz, 2H), 6.92 (dd, J=12.2, 8.4 Hz, 2H), 6.80 (d, J=9.6 Hz, 2H), 5.81 (s, 1H), 3.87 (q, J=7.0 Hz, 2H), 3.43 (d, J=7.1 Hz, 2H), 3.38 (s, 3H), 3.00 (q, J=7.4 Hz, 2H), 1.22 (t, J=7.4 Hz, 3H), 1.14 (t, J=7.0 Hz, 3H), 0.81 (d, J=7.8 Hz, 1H), 0.33 (dd, J=8.0, 1.2 Hz, 2H), 0.01 (d, J=5.9 Hz, 2H). MS (ESI+) m/z 519.2 (M+H)+.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13].[OH-].[K+]>C1C=CC=CC=1.C(O)C>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)CCCCNc1ccccc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCO
Product: O=C(O)CCCCNc1ccccc1-c1ccccc1
Reaction time: 24 h
Yield: 77.3 %

Procedure:
A solution of 8.0 g of ethyl 5-(biphenyl-2-yl)amino-valerate (see Example 53) in 60 ml of benzene is mixed with a solution of 2.2 g of potassium hydroxide in 20 ml of ethanol. After allowing the resulting admixture to stand for 24 hours at room temperature, the solvent mixture is distilled off in vacuo. The residue is then dissolved in water; the obtained aqueous solution is washed with diethyl ether and then acidified with dilute hydrochloric acid. The formed precipitate, which is oily at first, is taken up in dichloromethane. The solvent is then distilled off and the residue recrystallized from ethyl acetate/petrol ether (1:1) to obtain 5.6 g (77.3% of theory) of 5-[N-(biphenyl-2-yl)amino]valeric acid, MP 73° to 75°.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1F)[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][C:8]1([CH3:10])[O:7][C:6](=[O:12])[C:5]2[CH:13]=[CH:14][C:2]([O:1][C:23]3[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][C:16]=3[F:15])=[CH:3][C:4]=2[O:9]1
Reactant: CC1(C)OC(=O)c2ccc(O)cc2O1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC(=O)c2ccc(Oc3ccc(C=O)cc3F)cc2O1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
7-Hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one (I-1a: 12.9 g), 3,4-difluorobenzaldehyde (9.45 g) and potassium carbonate (27.6 g) were combined in dimethylformamide (100 mL) and stirred as the reaction mixture was heated to 80° C. After 24 hours, the reaction mixture was cooled to ambient temperature, combined with water, and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and evaporated. The residue was purified by column chromatography on silica gel eluting with 10-15% ethyl acetate in heptane to give the title compound (I-1b-1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11].C(NC(C)C)(C)C>C(OC(C)C)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][C:5]1[N:4]=[CH:3][C:2]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])=[CH:7][N:6]=1
Reactant: Cc1ncc(Br)cn1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CC(=O)OC(C)C
Product: Cc1ncc(C#C[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Isopropyl acetate (30 mL) was added to a mixture of 5-bromo-2-methylpyrimidine (3 g, 17.3 mmol), copper(I) iodide (0.066 g, 0.35 mmol) and bis(triphenylphosphine)palladium (II) dichloride (0.243 g, 0.35 mmol) in a 100 mL 3-neck flask equipped with a condenser. The resulting solution was sparged with a stream of nitrogen for 15 minutes and kept under nitrogen during further manipulations. Trimethylsilylacetylene (3.12 mL, 22.5 mmol) and diisopropylamine (4.90 mL, 34.7 mmol) were added successively to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The dark mixture was heated at 60° C. for 15 hours, then cooled to room temperature, diluted with isopropyl acetate (15 mL) and filtered through diatomaceous earth. The filtrate was washed successively with saturated aqueous NaHCO3 (2×25 mL), 10% aqueous Na2S2O3 (20 mL) and brine, then dried (MgSO4) and concentrated under vacuum. The dark residue was purified by flash chromatography on silca gel (hexanes-ethyl acetate, gradient from 100:0-70:30) to provide the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 0.27 (s, 9H), 2.74 (s, 3H), 8.68 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[NH2:22].Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[F:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:22][C:21]3[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:19]([O:18][CH3:17])[CH:20]=3)=[C:3]([C:15]#[N:16])[CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1F
Reactant: COc1cc(N)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2c(Nc3cc(OC)c(OC)c(OC)c3)c(C#N)cnc2cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
A mixture of 4-chloro-7-fluoro-6-methoxy-3-quinolinecarbonitrile (500 mg, 2.11 mmol), 3,4,5-trimethoxyaniline (515 mg, 2.81 mmol) and pyridine hydrochloride (270 mg , 2.33 mmol) in 20 mL of 2-ethoxyethanol is heated at reflux for 4 hours then cooled to room temperature. The reaction mixture is poured into aqueous sodium bicarbonate and stirred at room temperature for 15 minutes. The solid is collected by filtration and partitioned between water and ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Trituration of the residue with ethyl acetate and diethyl ether provides 512 mg of 7-fluoro-6-methoxy-4-[(3,4,5-trimethoxyphenyl)amino]-3-quinolinecarbonitrile, mp 215-217° C.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.OS(O)(=O)=O.[C:17](OC(C)=C)(=[O:19])[CH3:18]>>[C:17]([O:10][C:9]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][CH:11]=1)(=[O:19])[CH3:18]
Reactant: O=C1CCCc2ccccc21
Reactant: C=C(C)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)OC1=CCCc2ccccc21
Temperature: 25 °C
Yield: 112.3 %

Procedure:
A mixture of α-tetralone (200 mL, 1.5 mol) and conc. H2SO4 (4 mL) in isopropenyl acetate (1.0 L, 9.08 mol) was heated to reflux overnight. It was cooled to r.t. and filtered through a mixture of celite, NaHCO3 and silica (approx. 1:1:0.2) with EtOAc and concentrated to yield 317.1 g of the crude title product; bp: 90° C./0.5 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]2[CH3:24])[C:5]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.ClC1N=C(Cl)C2CN(C(OC(C)(C)C)=O)CC=2N=1.C[C@@H]1COCCN1>>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@H:19]2[CH3:24])[C:5]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C(=O)OC(C)(C)C)C2
Agent: CC(C)(C)OC(=O)N1Cc2nc(Cl)nc(Cl)c2C1
Agent: C[C@@H]1COCCN1
Product: C[C@@H]1COCCN1c1nc(Cl)nc2c1CN(C(=O)OC(C)(C)C)C2

Procedure:
Method as (S)-tert-butyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 1) using tert-butyl 2,4-dichloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate and (R)-3-methylmorpholine as starting materials to yield (R)-tert-butyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate a white solid (4.55 g, 12.8 mmol, 70%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2-c2ccc(Cl)cc2)CC1

Procedure:
4′-Chlorobiphenyl-2-carboxaldehyde (4.1 g), tert-butyl piperazine-1-carboxylate (4.23 g) and sodium triacetoxyborohydride (5.61 g) in CH2Cl2 (60 mL) were stirred for 24 hours. The mixture was treated with methanol and poured into ether. The extract was washed with water and brine and concentrated. The concentrate was chromatographed on silica gel with 2-25% ethyl acetate/hexanes.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]3[CH:11]=[N:12][N:13](CC4C=CC(OC)=CC=4)[C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=1.[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[C:37]([NH2:39])[CH:36]=[C:35]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[N:34]=2)[CH2:29][CH2:28]1.C1(OC)C=CC=CC=1>>[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[C:37]([NH:39][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:17]=[CH:16][CH:15]=[C:14]5[C:10]=4[CH:11]=[N:12][NH:13]5)[CH:5]=[CH:4][N:3]=3)[CH:36]=[C:35]([N:40]3[CH2:41][CH2:42][O:43][CH2:44][CH2:45]3)[N:34]=2)[CH2:29][CH2:28]1
Reactant: Nc1cc(N2CCOCC2)nc(N2CCOCC2)c1
Reactant: COc1ccc(Cn2ncc3c(Nc4ccnc(Cl)n4)cccc32)cc1
Solvent: COc1ccccc1
Product: c1cc(Nc2ccnc(Nc3cc(N4CCOCC4)nc(N4CCOCC4)c3)n2)c2cn[nH]c2c1
Temperature: 130 °C
Yield: 34.5 %

Procedure:
N-(2-chloropyrimidin-4-yl)-1-(4-methoxybenzyl)-1H-indazol-4-amine (400 mg, 1.09 mmol) and 2,6-dimorpholinopyridin-4-amine (289 mg, 1.09 mmol) were reacted according to procedure of Example 1. After filtration of the solids and evaporation of the solvents, the resulting gum was dissolved in TFA (8.2 mL) and anisole (0.594 mL, 5.47 mmol) and sealed into a microwave tube. The reaction was heated to 130° C. over a period of 30 minutes in a Personal Chemistry EMRYS™ Optimizer EXP microwave synthesisor. The reaction mixture was concentrated to dryness, diluted with dichloromethane (20 ml), washed with water (20 ml), brine (20 ml), dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in dichloromethane. The solvent was evaporated to dryness. The resulting solid was triturated with diethyl ether/petroleum ether (1/1), collected by filtration and dried under vacuum to give N2-(2,6-dimorpholinopyridin-4-yl)-N4-(1H-indazol-4-yl)pyrimidine-2,4-diamine (178 mg, 34.4%) as a pale beige solid. NMR Spectrum: (DMSOd6) 3.17 (bs, 8H), 3.61 (bs, 8H), 6.47 (s, 1H), 6.59 (s, 2H), 7.22 (s, 1H), 7.27 (s, 1H), 7.79 (s, 1H), 8.12 (s, 1H), 8.21 (s, 1H), 9.16 (s, 1H), 9.46 (s, 1H), 13.06 (s, 1H); Mass spectrum: MH+ 474.
Reaction SMILES: CN(C=O)C.C(OC([N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23](O)=O)[CH:19]=2)[CH2:14]1)=O)(C)(C)C.C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[C:34](=[S:48])[NH:35][C:36]([C:39]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:41][CH2:40]2)=[CH:37][CH:38]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)Cl.C1(C)C=CC=CC=1>[C:42]1([C:39]2([C:36]3[N:35]=[C:34]4[S:48][C:23]([C:18]5[CH:19]=[C:20]6[C:15](=[CH:16][CH:17]=5)[CH2:14][NH:13][CH2:22][CH2:21]6)=[N:32][C:33]4=[CH:38][CH:37]=3)[CH2:40][CH2:41]2)[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: Nc1ccc(C2(c3ccccc3)CC2)[nH]c1=S
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)O)ccc2C1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: c1ccc(C2(c3ccc4nc(-c5ccc6c(c5)CCNC6)sc4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DMF (27.8 μL, 0.358 mmol) was added to a solution of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (198.6 mg, 0.716 mmol) and oxalyl chloride (66 μL, 0.757 mmol) in DCM (7.0 mL), and the resulting mixture was stirred at 25° C. for 4 h. The reaction mixture was then concentrated in vacuo and 3-amino-6-(1-phenylcyclopropyl)pyridine-2(1H)-thione (175 mg, 0.720 mmol) was added. The resulting mixture was taken up in toluene (7.0 mL) and stirred at 25° C. for 5 min then at 100° C. for 1.5 h. (±)-10-camphorsulfonic acid (184 mg, 0.792 mmol) was then added, and the resulting mixture was heated at 100° C. for 1.5 h. The reaction mixture was subsequently cooled to 25° C. and purified by column chromatography (silica gel, 0-10% MeOH/DCM) to provide crude product, which was taken up in DCM (100 mL) and sequentially washed with sat. aq. NaHCO3 and brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 5-(1-phenylcyclopropyl)-2-(1,2,3,4-tetrahydroisoquinolin-6-yl)thiazolo[5,4-b]pyridine as a light yellow solid. MS (ESI) m/z: Calculated: 383.1; Observed: 384.1 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]>[Cl-].[Zn+2].[Cl-].C1(=O)CCCCC1>[Cl:10][C:8]1[CH:9]=[C:2]2[C:3](=[CH:6][CH:7]=1)[C:4]([NH2:5])=[C:3]1[C:2]([CH2:9][CH2:8][CH2:7][CH2:6]1)=[N:1]2
Reactant: N#Cc1ccc(Cl)cc1N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=C1CCCCC1
Product: Nc1c2c(nc3cc(Cl)ccc13)CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
2-Amino-4-chlorobenzonitrile (5.0 g, 33 mmolL), cyclohexanone (30 ml) and Zinc chloride (4.8 g, 35 mmoL) were mixed in a round bottomed flask and heated up to 120 degree Celsius for 3 hours. After cooling to room temperature, the solvent was decanted off. The resulting residue was triturated with ethyl acetate (30 ml). The solid was collected by filtration and added into 10% aqueous NaOH (50 ml). After stiring for 2 hours, the mixture was filtered and the filter cake was washed thoroughly with water. The filter cake was then extracted with methanol. The combined methanolic extract was concentrated to produce the desired product (3.8 g, 16 mmoL) in 48% yield.
Reaction SMILES: C([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:12]=2)[CH2:7][CH2:6]1)(=O)C.[ClH:23]>>[ClH:23].[NH2:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]([F:21])([F:22])[F:20])[N:12]=2)[CH2:9][CH2:10]1
Reactant: CC(=O)NC1CCN(c2cccc(OCC(F)(F)F)n2)CC1
Agent: Cl
Product: NC1CCN(c2cccc(OCC(F)(F)F)n2)CC1

Procedure:
By heating the 4-acetamido-1-[6-(2,2,2-trifluoro) ethoxy-2-pyridyl]piperidine at reflux for 3 hours in an 0.5 N solution of hydrochloric acid and then operating as described in Example 1, the monohydrochloride of 4-amino-1-[6-(2,2,2-trifluoro)ethoxy-2-pyridyl] piperidine (CM 57385) is obtained which, after crystallation in ethanol, melts at 218° to 225° C. with decomposition.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=1.[CH:16]1([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17]1.[H-].[Na+]>C(O)(=O)C>[CH:16]1([O:21][C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: OC1CCCC1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(OC2CCCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To 30 ml of N,N-dimethylformamide, 1.00 g (6.4 mmol) of 6-chloronicotinic acid and 1.72 g (20 mmol) of cyclopentanol were dissolved, followed by adding 0.80 g (20 mmol) of 60% sodium hydride, stirring at room temperature for 1 hour and heating under refluxing for 3 hours. The reaction liquid was then poured in 100 ml of ice water and acetic acid was added to make pH 5. The crystal precipitated was filtered, washed with cold water and hexane, and dried to obtain 1.06 g (yield: 80%) of 6-cyclopentyloxynicotinic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:13]=[N:14][C:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:16][CH:17]=2)(O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:13]=[N:14][C:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:16][CH:17]=2)=[CH:9]\[CH3:10])=[CH:4][CH:3]=1
Reactant: CCC(O)(c1ccc(F)cc1)c1cnc(N2CCNCC2)nc1
Agent: Cl
Solvent: C1COCCO1
Product: C/C=C(\c1ccc(F)cc1)c1cnc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.3 %

Procedure:
To a solution of 1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)propan-1-ol (200 mg, 0.6 mmol) in dioxane (10 mL) was added HCl in dioxane (4 M, 10 mL), and the reaction was stirred at RT for 1 h. LCMS showed the reaction was completed. The mixture was concentrated to an oil, which was purified by Combiflash with dichloromethane:methanol=20:1 to give the title compound as a light yellow solid (185 mg, 98%). MS (ES+) C17H19FN4 requires: 298. found: 299 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[NH:11][CH:12]=[CH:13][CH:14]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:8]([C:10]1[NH:11][CH:12]=[CH:13][CH:14]=1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)c1ccc[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CCc2ccc[nH]2)cc1

Procedure:
Compound (III) is dissolved in an ethereal solvent, preferably anhydrous tetrahydrofuran, and a complex metal hydride, preferably lithium aluminum hydride, is added. The mixture is reacted at reflux temperature for 35-53 hours, preferably 48 hours. Excess of hydride is destroyed with organic solvent and the reaction mixture is purified by methods known to the art to afford 2-[phenethyl]pyrrole (IV).
Reaction SMILES: C([Li])CCC.CCCCCC.CCN(C(C)C)C(C)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:36]=[C:35]3[C:30]([CH:31]=[CH:32][CH:33]=[CH:34]3)=[N:29]2)=[CH:24][CH:23]=1.[CH:37]1([CH:43]=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C1COCC1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:36]([CH:43]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[OH:44])=[C:35]3[C:30]([CH:31]=[CH:32][CH:33]=[CH:34]3)=[N:29]2)=[CH:24][CH:23]=1
Reactant: O=CC1CCCCC1
Reactant: Clc1ccc(-n2cc3ccccc3n2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Product: OC(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
A 1.6 M solution of n-butyllithium in hexane (5.7 ml, 9.1 mmol) was added within 10 min to a −78° C. cold solution of N,N′-diisopropylethylamine (1.55 ml, 9.1 mmol) in THF (25.5 ml). The solution was stirred for 10 min at 5° C. and cooled again to −78° C. A solution of 2-(4-chloro-phenyl)-2H-indazole (1.7 g, 7.4 mmol; Liu, Rui; Zhu, Yong-ming; Qin, Lie-na; Ji, Shun-jun; Katayama, Haji. Heterocycles (2007), 71(8), 1755-1763.) in THF (8.5 ml) was added, the suspension was stirred for 15 min at 0° C., cooled to −78° C. and cyclohexane-carbaldehyde (1.1 ml, 9.1 mmol; CAS Reg. No. 2043-61-0) was added. The reaction mixture was stirred at ambient temperature for 14 h. Under ice cooling saturated aqueous ammonium chloride solution was added and the mixture was extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (1.1 g, 3.2 mmol; 43%) as yellow foam. MS: m/e=341.2 [M+H+].
Reaction SMILES: [OH-].[K+].[CH3:3][SH-:4][C:5](=[N:7][OH:8])[CH3:6].C1C=CC=CC=1.[CH3:15][N:16]([S:20][N:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:17](F)=[O:18]>C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3.O>[CH3:15][N:16]([S:20][N:21]([CH:22]([CH3:24])[CH3:23])[CH:25]([CH3:26])[CH3:27])[C:17]([O:8][N:7]=[C:5]([S:4][CH3:3])[CH3:6])=[O:18]
Reactant: C[SH-]C(C)=NO
Reactant: CC(C)N(SN(C)C(=O)F)C(C)C
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CSC(C)=NOC(=O)N(C)SN(C(C)C)C(C)C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
Powdered potassium hydroxide (2.5 g), 4.7 g. 10.045 mole) of S-methyl-N-hydroxythioacetimidate, 0.11 g dicyclohexyl-18-crown-6, and benzene (200 mol) were combined and stirred 0.5 hr. at room temperature. Then 9.4 g (0.045 mole) of N-methyl-N-(diisopropylaminosulfenyl)carbamoyl fluoride were added. The mixure was stirred at room temperature for 1 hr., and then was water washed four times, dried (MgSO4), and the benzene solvent was removed under vacuum. The residue was recrystallized from diisopropyl ether to give 9 g (67.3 percent yield) of S-methyl N-[N'-methyl-N'-(diisopropylaminosulfenyl)carbamoyloxy]thioacetimidate, m.p. 79°-80° C.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([Cl:17])[CH:12]=3)[C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1>S(=O)(=O)(O)O.[Cu]>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([Cl:17])[CH:12]=3)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccc(Cl)cc2C(=O)c2c(Cl)cccc21
Agent: [Cu]
Agent: O=S(=O)(O)O
Product: O=C1c2cc(Cl)ccc2Cc2cccc(Cl)c21
Temperature: 40 °C
Reaction time: 5 h

Procedure:
Copper powder (1 g.) is added to 1,7-dichloroanthraquinone (1.25 g.) in concentrated sulphuric acid (10 ml.) and the mixture is stirred at 40°C. for 5 hours then poured into ice-water and extracted with ethyl acetate. The ethyl acetate extract is washed with water and with brine, dried (MgSO4) and evaporated to give 1,7-dichloroanthrone, m.p. 160°-165°C. on recrystallisation from acetic acid.