Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH:2]1[C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5][CH2:4][C:3]1([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:12]=[O:13].[BH4-].[Na+]>CO>[CH2:10]1[CH2:9][O:8][C:7]2([CH2:6][CH2:5][CH2:4][C:3]([CH2:12][OH:13])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:2]2)[O:11]1
Reactant: CC1C2(CCCC1(C=O)c1ccccc1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC1(c2ccccc2)CCCC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a solution of methyl 3,3-ethylenedioxy-1-phenylcyclohexanecarbaldehyde (1.43 g, 5.81 mmol) in methanol (25 mL) at 0° C. was added sodium borohydride (221 mg) in portions, and the resulting suspension was stirred at room temperature overnight. The reaction was quenched with saturated sodium bicarbonate and methanol was removed under vacuum. The aqueous layer was extracted with dichloromethane 3 times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as clear colorless sticky oil (1.25 g, 87% yield). 1H NMR (400 MHz, CDCl3) δ 1.48–1.81 (7H, m), 1.88 (1H, d, J=16 Hz), 2.06 (1H, d, J=12 Hz), 2.22 (1H, d, J=12 Hz), 3.73–4.06 (5H, m), 7.15–7.25 (2m), 7.31–7.38 (3H, m). HPLC purity (retention time): 85% (1.44 min, method C). MS: 271.40 (M+Na+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]1[O:21][C@@H:19]1[CH3:20]>>[OH:21][C@H:19]([CH3:20])[CH2:18][N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:17]=2)[CH:13]=[CH:14]1
Reactant: c1ccc(COc2ccc3cc[nH]c3c2)cc1
Reactant: C[C@@H]1CO1
Product: C[C@@H](O)Cn1ccc2ccc(OCc3ccccc3)cc21

Procedure:
Alternatively, compound 1 is reacted with (R)-propylene oxide according to the foregoing method to yield (R)-1-(2-hydroxypropyl)-6-benzyloxyindole (R-2). Alternatively, compound 1 is reacted with (S)-propylene oxide according to the foregoing method to yield (S)-1-(2-hydroxypropyl)-6-benzyloxyindole (S-2).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:21]3[CH2:22][C:8]4([CH2:12][N:11]([CH2:13][CH:14]5[CH2:18][CH2:17][CH2:16][CH2:15]5)[CH2:10][CH:9]4[C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=43)[C:7]=2[CH:27]=1)=O.Cl.[NH2:29][OH:30].[OH-].[Na+]>C(O)C.O>[CH:1](=[N:29][OH:30])[C:3]1[CH:4]=[CH:5][C:6]2[CH:21]3[CH2:22][C:8]4([CH2:12][N:11]([CH2:13][CH:14]5[CH2:18][CH2:17][CH2:16][CH2:15]5)[CH2:10][CH:9]4[C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=43)[C:7]=2[CH:27]=1
Reactant: O=Cc1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Reaction time: 0.5 h

Procedure:
To a suspension of 6.6 g (0.02 mole) of 5-formyl-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole (Example 69) and 2.0 g (0.03 mole) of hydroxylamine hydrochloride in 25 ml of ethanol was added dropwise a solution of 1.6 g (.04 mole) of sodium hydroxide in 5 ml of water. The reaction mixture was stirred for 30 minutes and heated under reflux for 5 minutes. A yellow solid precipitated. The reaction mixture was diluted with water, extracted with methylene chloride, and the extract was dried over potassium carbonate and concentrated. The resulting oil was dissolved in ether and filtered. Evaporation of the ether gave the product, 5-formyl-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole oxime, as an oil which was crystallized by the addition of pet. ether. The oxime was dissolved in ether and the solution was acidified to give 3.8 g of the hydrochloride salt; mp. 200° -205° (with dec. starting at 185°).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C1([O:11][C:12](=O)[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([C:22]3[C:30]4[C:29]([NH2:31])=[N:28][CH:27]=[N:26][C:25]=4[N:24]([CH:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:23]=3)=[O:21])[CH:15]=2)C=CC=CC=1>C1COCC1>[NH2:31][C:29]1[C:30]2[C:22]([C:20]([C:16]3[CH:15]=[C:14]([NH:13][C:12]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:11])[CH:19]=[CH:18][CH:17]=3)=[O:21])=[CH:23][N:24]([CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[C:25]=2[N:26]=[CH:27][N:28]=1
Reactant: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)Oc3ccccc3)c1)cn2C1CCCC1
Reactant: NC1CC1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)NC3CC3)c1)cn2C1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Cyclopropyl amine (130 mg, 2.3 mmol) was added to a solution of [3-(4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-carbamic acid phenyl ester (50 mg, 0.11 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo. Purification by flash column chromatography (silica, 4:96→15:85 MeOH:CH2Cl2) provided the title compound as a pale yellow solid (44 mg, 95%). MS: 405.2 (MH+); HPLC Rf: 4.73 min. (HPLC method 4); HPLC purity: 100%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:20])[CH2:10][C:11]1[NH:15][C:14]2[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=2[N:12]=1.C[O-].[Na+].[C:24](OC)(=[O:27])[C:25]#[CH:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([C:10]1[CH:26]=[CH:25][C:24](=[O:27])[N:15]2[C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[NH:12][C:11]=12)=[O:20]
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1cc(F)ccc1F
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: O=C(c1cc(F)ccc1F)c1ccc(=O)n2c3c([nH]c12)CCCC3

Procedure:
The compound is prepared as described in example 20 with 500 mg (1.81 mmol) of 1-(2,5-Difluorophenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone (example XXXXII), 195.5 mg (3.62 mmol) of sodium methylate and 152.2 mg (1.81 mmol) methyl propiolate.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][NH:11][CH:10]1[C:22]#[N:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CC(C)=O>[CH2:32]([N:11]1[CH2:12][C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]1[C:22]#[N:23])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: N#CC1NC[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CC1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)CN1Cc1ccccc1

Procedure:
A mixture of (3R,4R)-3,4-dibenzyloxy-pyrrolidine-2-carbonitrile (13 g, 42.2 mmol), potassium carbonate (8.7 g, 63 mmol), potassium iodide (0.1 g), benzyl bromide (7.5 ml, 63.2 mmol) and acetone (200 ml) were heated at reflux temperature for 4 hours. The mixture was cooled, filtered and the filtrate evaporated to dryness in vacuo to give the title compound as an oil. Purification of the crude product on a silica gel column (Eluent: From 100% heptane to 100% ethyl acetate) afforded (3R,4R)-1-benzyl-3,4-dibenzyloxy-pyrrolidine-2-carbonitrile (8.2 g, yield: 49%) as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[N:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CC(C)=O>[N:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:2][C:3]2[S:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: ClCc1cccs1
Reactant: O=NN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=NN1CCN(Cc2cccs2)CC1
Yield: 91.5 %

Procedure:
2-Chloromethylthiophene (prepared as described by F. F. Blicke and J. H. Burkhatter in J. Amer. Chem. Soc., 64, 477, 1947) (5.0 g, 0.038 mole) was added to acetone (100 ml) containing N-nitrosopiperazine (5.4 g, 0.038 mole) (prepared as described in U.S. Pat. No. 2,907,767), anhydrous potassium carbonate (6.0 g, 0.04 mole) and a catalytic amount of potassium iodide (1 small crystal). The mixture was heated under reflux for 3 hours, cooled, treated with water (50 ml) evaporated to 1/3 volume and extracted with ethylacetate (3×150 ml). The combined extracts were dried (anhydrous K2CO3), filtered and evaporated in vacuo to yield N-nitroso-N'-2-thenylpiperazine (7.35 g, >99%) as a straw coloured oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([Br:13])[C:8]([I:14])=[C:7]([CH3:15])[C:3]=1[C:4]([OH:6])=[O:5].[O:16]1CCC[CH2:17]1>>[Br:13][C:9]1[C:8]([I:14])=[C:7]([CH3:15])[C:3]2[C:4](=[O:6])[O:5][C:17](=[O:16])[NH:1][C:2]=2[C:10]=1[O:11][CH3:12]
Reactant: COc1c(N)c(C(=O)O)c(C)c(I)c1Br
Reactant: C1CCOC1
Product: COc1c(Br)c(I)c(C)c2c(=O)oc(=O)[nH]c12
Temperature: 40 °C
Reaction time: 1 h

Procedure:
According to the same method as in Reference Example 31, 2-amino-4-bromo-5-iodo-3-methoxy-6-methylbenzoic acid (I-4) (3.42 g, 8.86 mmol) and bis(trichloromethyl) carbamate (893 mg, 3.01 mmol) were dissolved in dewatered tetrahydrofuran (70 ml) under nitrogen atmosphere, followed by stirring at 40° C. for 1 hour. The reaction liquid was concentrated under reduced pressure to obtain the entitled compound (3.89 g, quant.) as a pale brown solid. Not further purified, this was used in the next reaction.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[O:18]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.N1C=CC=CC=1.C(OCCO)C>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:28][C:27]1[CH:29]=[CH:30][CH:31]=[C:25]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:26]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1cccc(Oc2ccccc2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3cccc(Oc4ccccc4)c3)c2cc1OC
Temperature: 139 °C
Yield: 77.8 %

Procedure:
A mixture of 0.248 g (1 mmol)of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.204 g (1.1 mmol) of 3-phenoxyaniline, 0.116 g (1 mmol) pyridine hydrochloride and 12 ml of 2-ethoxyethanol was heated in a 138-140° C. oil bath for 3 hours; progress of the reaction was monitored by TLC. When TLC indicated the disappearance of starting material, the reaction was cooled and concentrated in vacuo to a thick oil. To this oil was added 50 ml of water followed by 5 ml of 1M NaHCO3, approximately pH 8. The resulting precipitate was collected, washed with water and diethyl ether, and dried in vacuo at 65° C. to give 0.309 g (78%) of the desired product as cream crystals. MP 253-254° C.; : mass spectrum (electrospray, m/e,): 397.0(M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([N:47]3[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]3)=[O:21])([CH2:14][CH2:13]1)[CH2:18][CH2:19]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)C23CCC(N(CC(=O)N4C[C@@H](F)C[C@H]4C#N)C(=O)OCc4ccccc4)(CC2)CC3)CC1

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-methylpiperazine (14.5 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(4-methylpiperazin-1-yl)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (36.0 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C>[CH2:13]1[CH:14]2[N:10]([CH2:2][CH:3]=[C:4]([C:3]3[C:4]4[C:9](=[N:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:5]2)[CH2:11][CH2:12]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: C1CCNC1
Solvent: CCO
Product: C1=C(c2c[nH]c3ncccc23)CC2CCCN2C1

Procedure:
from 7-azaindole (500 mg, 4.2 mmol), 1,2,3,5,6,8,8a-heptahydrohydro-7-oxo-indolizine (589 mg, 4.2 mmol) and pyrrolidine (3.0 g, 42 mmol) in ethanol (4 mL) heating at reflux for 5 hrs.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10](I)[C:11]([NH2:14])=[N:12][CH:13]=1.[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>O1CCOCC1>[Br:7][C:8]1[CH:9]=[C:10]([C:21]2[CH:22]=[N:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:11]([NH2:14])=[N:12][CH:13]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Nc1ncc(Br)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(Br)cnc2N)cn1
Temperature: 120 °C
Reaction time: 14 h

Procedure:
I2 (8.81 g, 34.7 mmol, 1.2 equiv.) was added to a solution of 5-bromopyridin-2-amine (5.00 g, 28.9 mmol) in DMSO (30 mL), and the resulting mixture was stirred at 100° C. for 4 h. After standing at 25° C. for 12 h, the reaction mixture was poured onto a saturated Na2S2O5 aqueous solution (20 mL), and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc, EtOAc 15 to 25%) providing 5-bromo-3-iodopyridin-2-amine (4.00 g, 46%) as a pale yellow solid. H1 NMR (300 MHz, CDCl3): δ 8.07 (s, 1H), 7.98 (s, 1H) and 5.05 (bs, 2H). K2CO3 aqueous solution (1 M, 6.8 mL) was added to a suspension of 5-bromo-3-iodopyridin-2-amine (2.00 g, 6.69 mmol), 6-methoxypyridin-3-ylboronic acid (1.12 g, 7.32 s mmol, 1.1 equiv.), and Pd(PPh)3 (380 mg, 5 mol %) in dioxane (20 mL) under N2. The reaction mixture was stirred at 120° C. for 14 h, poured onto H2O (65 mL) and extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc, EtOAc 30 to 40%) providing intermediate 5-bromo-3-(6-methoxypyridin-3-yl)pyridin-2-amine (1′) (Formula iv) (993 mg, 53%) as a pale yellow solid.
Reaction SMILES: C([NH:5][S:6]([C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:10]=1[C:18]([O-:20])=[O:19])(=[O:8])=[O:7])(C)(C)C.Cl.[CH3:22]O>>[NH2:5][S:6]([C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:10]=1[C:18]([O:20][CH3:22])=[O:19])(=[O:8])=[O:7]
Reactant: CC(C)(C)NS(=O)(=O)c1c(C(=O)[O-])sc2ccccc12
Reactant: CO
Agent: Cl
Product: COC(=O)c1sc2ccccc2c1S(N)(=O)=O

Procedure:
A solution of 6 g of 3-tert-butylaminosulfonylbenzothiophene-2-carboxylate acid in 100 ml of methanol was saturated with anhydrous hydrogen chloride and then heated to reflux for three hours. The mixture was evaporated in vacuo to half of its volume and the residue poured into 200 g of ice and filtered to yield the desired product melting at 150°-154°. The infrared absorption spectrum shown by this material was qualitatively equivalent to that of the product of Example 4.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4]([Cl:12])[N:3]=1.CCN(C(C)C)C(C)C.[CH:22]([O:25][C:26]1[NH:30][N:29]=[C:28]([NH2:31])[CH:27]=1)([CH3:24])[CH3:23]>C1COCC1>[Cl:8][C:7]1[C:2]([NH:31][C:28]2[CH:27]=[C:26]([O:25][CH:22]([CH3:24])[CH3:23])[NH:30][N:29]=2)=[N:3][C:4]([Cl:12])=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: CC(C)Oc1cc(N)n[nH]1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Nc2nc(Cl)c([N+](=O)[O-])cc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 120 h
Yield: 18.1 %

Procedure:
To a mixture of 2,3,6-trichloro-5-nitropyridine (2.61 g, 11.4 mmol) and DIEA (1.90 ml, 11.4 mmol) in THF (50 ml) was added 5-isopropoxy-1H-pyrazol-3-amine (1.20 g, 8.50 mmol) at 0° C. After addition, the reaction mixture was stirred at 25° C. for 5 days. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane-EtOAc=1:1) to give the title compound as a yellow solid (0.51 g, 18%). 1H NMR (400 MHz) δ 12.22 & 11.35 (s, 1H), 10.12 & 9.80 (s, 1H), 8.64 & 8.54 (s, 1H), 5.95 & 5.84 (s, 1H), 4.70 & 4.46 (m, 1H), 1.27-1.32 (m, 6H). MS: Calcd.: 331. Found: [M+H]+ 332.
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[CH2:24][CH2:25][NH2:26]>C(O)C>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]2[C:7](=[O:17])[C:6](=[O:18])[C:5]=2[NH:26][CH2:25][CH2:24][C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Reactant: NCCc1cccc(C(F)(F)F)c1
Solvent: CCO
Product: COc1ccc(-c2c(NCCc3cccc(C(F)(F)F)c3)c(=O)c2=O)cc1
Yield: 67.8 %

Procedure:
In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) and 3-trifluoromethylphenethyl-amine (0.23 g, 1.22 mmol) in ethanol (3 mL) were converted to the title compound (0.155 g, 68%) m.p.: 220.2-222.3° C.; 1H NMR (DMSO-d6) δ9.05(br t,1H), 7.95(ABq,2H), 7.60-7.45(m,4H), 7.08(ABq,2H), 3.94(br t,2H), 3.83(s,3H), 3.04(t,3H); IR (KBr) 3210, 3170, 1775, 1780, 1575, 1360, 1325, 1175, 1125, 1070, 1020, 840, 800, 695 cm−1; MS (m/z) 375 [M+].
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][CH2:12][C:13]1[C:17](=[O:18])[O:16][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=O)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(O)(=O)C>[C:15]([NH:14][CH:13]([CH2:12][CH2:11][CH2:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:17](=[O:18])[CH3:25])(=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1OC(c2ccccc2)N=C1CCCNC(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(=O)C(CCCNC(=O)c1ccccc1)NC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 4-(3-benzamidopropyl)-2-phenyl-5-oxazolone (1.0 g, 3.1 m.mol), 4-dimethylaminopyridine (0.016 g), acetic anhydride (0.62 ml) and triethylamine (0.62 ml) was stirred for one hour. Acetic acid (4.7 ml) was added and the solution was set aside overnight and evaporated to dryness. The residue was dissolved in chloroform and washed with dilute NaOH, dilute HCl and then dried over MgSO4. Concentration gave the crude product which could be purified by dry-column chromatography on alumina with ethyl acetate as solvent to give 3,6-dibenzamidohexan-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:14])[C:10]=1[O:11][CH2:12][CH3:13])C(O)=O.[H-].[Na+].ICC.C[N:21](C=O)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:14])[C:10]=1[O:11][CH2:12][CH3:13])[NH2:21]
Reactant: CCOc1c(Cl)cc(C(=O)O)cc1Cl
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Product: CCOc1c(Cl)cc(N)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
4-Amino-2,6-dichlorophenol (1) (1.00 g, 5.62 mmol) was dissolved in dry DMF (9 mL) and cooled to 0° C. Sodium hydride (142 mg, 5.90 mmol) was added to the mixture portionwise. The dark purple solution was stirred for 1 h at RT, then iodoethane (468 μL, 5.79 mmol) was added. The reaction mixture was stirred for 3 h and partitioned between EtOAc and aqueous NaOH (1 M). The organic layer was washed successively with water and brine, and then dried over MgSO4, filtered and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography (5% EtOAc/isohexane) to afford 3,5-dichloro-4-ethoxyaniline (2) (460 mg, 40%): m/z 206 [M+H]+ (ES+). 1H NMR (400 MHz, CDCl3) δ: 6.60 (2H, s), 4.01 (2H, q), 3.60 (2H, s), 1.42 (3H, t).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][N:20]2[C:25](=[O:26])[CH:24]=[CH:23][N:22](COCC[Si](C)(C)C)[C:21]2=[O:35])[CH2:13][CH2:12]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:36][C:2]([F:1])([F:37])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][N:20]2[C:25](=[O:26])[CH:24]=[CH:23][NH:22][C:21]2=[O:35])[CH2:15][CH2:16]1
Reactant: C[Si](C)(C)CCOCn1ccc(=O)n(CCCN2CCN(c3ccccc3OCC(F)(F)F)CC2)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=c1cc[nH]c(=O)n1CCCN1CCN(c2ccccc2OCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
A mixture of the 3-(3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}-propyl)-1-[2-(trimethylsilyl)ethoxymethyl]-2,4(1H,3H)-pyrimidinedione (273 mg, 0.5 mmol), prepared as in Example 25, tetrabutylammonium fluoride (2 mmol) and THF (5 mL) was stirred 24 hours at 25° C. The reaction mixture then was concentrated and the residue was purified by column chromatography on silica gel eluting with ethyl acetate to give 3-(3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-2,4(1H,3H)-pyrimidinedione (160 mg, 0.39 mmol). The free base was recrystallized from a solution of hydrogen chloride in ethanol to give 3-(3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 247°-249° C. Anal.: Calcd. for C19H23F3N4O3.(HCl)2 : C, 47.01; H, 5.19; N, 11.54%; Found: C, 46.84; H, 5.18; N, 11.34%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C(N2C(=O)[C:47](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:46]([C:61]3C=CC(S(C)(=O)=O)=CC=3)[CH:45]=N2)C=CC=1.N>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:45][CH:46]([CH3:61])[CH3:47])=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3cccc(Cl)c3)c2=O)cc1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Agent: N
Product: CC(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone (prepared as an intermediate in Example 375) in place of 2-(3-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone (yield: 0.486 g, 100%). mp 121-128° C. 1H NMR (300 MHz, DMSO d6) δ 0.78 (d, J=7 Hz, 6H), 1.84 (m, 1H), 3.30 (s, 3H), 4.20 (d, J=6 Hz, 2H), 7.37 (m, 2H), 7.66 (m, 2H), 7.92 (m, 2H), 8.07 (m, 2H), 8.19 (s, 1H). MS (DCI/NH3) m/z 417 (M+H)+, 434 (M+NH4)+; Anal. calc. for C21H21FN2O4S.0.50H2O: C, 59.28; H, 5.21; N, 6.58. Found: C, 59.49; H, 4.97; N, 6.34
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.[CH3:33][O:34][C:35](=[O:40])[C:36](Br)([CH3:38])[CH3:37]>>[CH2:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([C:36]([CH3:38])([CH3:37])[C:35]([O:34][CH3:33])=[O:40])[CH2:4]4)[N:7]3[CH3:32])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: COC(=O)C(C)(C)Br
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(C)(C)C(=O)OC)C3)n(C)c2n1

Procedure:
Following General Procedure C, 4-(8-(azetidin-3-ylmethyl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine 530 was alkylated by 2-bromo-2-methyl-propionic acid methyl ester to give 532. LCMS m/z: 267.2 (2M+H+)