Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([CH3:17])[CH:9]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)Cl.O>[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)=[O:14])=[C:10]([CH3:17])[CH:9]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CN1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cc(Br)ccc1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.850 ml (10 mmol) oxalyl chloride in 20 ml CH2Cl2 is added dropwise to a iced-cooled solution of 1.10 g (5 mmol) 4-bromo-2-methylbenzoic acid in 30 ml CH2Cl2. After complete addition, the cooling bath is removed and stirring maintained for 1 h at RT. The solvent is evaporated to dryness, the resultant colorless residue is dried under vacuum and then diluted with 25 ml CH2Cl2. This solution is then added dropwise to a mixture of 1.01 g (10 mmol) of N-methylpiperazine in 25 ml CH2Cl2. After 1 h 30, the reaction mixture is diluted with water and the two phases are separated. The aqueous phase is re-extracted with CH2Cl2 and the combined organic extracts are successively washed with a sat.solution of NaHCO3, water, sat. brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo to afford, after drying in HV, the title compound which is used in the next step without further purification.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:8][CH:7]([NH:9]C(=O)OC(C)(C)C)[CH2:6]1)[CH:2]([CH3:4])[CH3:3].[ClH:17]>O1CCOCC1>[ClH:17].[CH2:1]([CH:5]1[CH2:8][CH:7]([NH2:9])[CH2:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC1CC(NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CC1CC(N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (3-isobutylcyclobutyl)carbamate (2.90 g) and dioxane (15 mL) were mixed. To the mixture was added a solution of 4 N hydrochloric acid in dioxane (15 mL) at 10° C. The mixture was stirred at RT overnight. The reaction mixture was concentrated in vacuo to give the title compound (1.97 g) as a crude product.
Reaction SMILES: I[C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][N:30]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:31]=2)O1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O>[C:32]([N:30]1[CH:31]=[C:27]([C:2]2[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=2)[CH:28]=[N:29]1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Nc1ccc(I)c(N)n1
Reactant: CC1(C)OB(c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)c(N)n1
Temperature: 95 °C
Reaction time: 2.5 h
Yield: 76 %

Procedure:
To a solution of 3-iodo-pyridin-2,6-diamine (3.3 g, 7.74 mmol, purity: 70%) described in Manufacturing Example 13-1-1 in toluene (50 mL) were added ethanol (25 mL), 2 N aqueous sodium carbonate solution (12.5 mL), 4-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)-1-trityl-1H-pyrazole (3.3 g, 7.56 mmol) described in Manufacturing Example 32-1-2 and tetrakis(triphenylphosphine)palladium (0) (1.02 g, 0.88 mmol) under nitrogen atmosphere, which was stirred for 2.5 hours at 95° C. Water and ethyl acetate were added to the reaction mixture at room temperature, which was then filtered through a Celite pad, and the filtrate was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:2 then 2:1 then 5:1) to obtain the title compound (2.4 g, 73%).
Reaction SMILES: [CH2:1]([C:3]1([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]CC(F)(F)C(F)(F)F)[C:22]([OH:24])=[O:23])[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2].[F:46][C:47]([F:70])([C:66]([F:69])([F:68])[F:67])CCCCCC(CCCCCC=C)C(OCC)=O>>[CH2:1]([C:3]1([C:39]2[CH:40]=[CH:41][C:42]([OH:45])=[CH:43][CH:44]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:47]([F:70])([F:46])[C:66]([F:69])([F:68])[F:67])[C:22]([OH:24])=[O:23])[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2]
Reactant: C=CCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Product: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 13 and the ethyl 2-(6,6,7,7,7-pentafluoroheptyl)-8-nonenoate prepared in Example 11, the same procedure as shown in Example 13 was repeated to give 10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoic acid.
Reaction SMILES: [CH2:1]([N:4]([CH3:9])[CH2:5][C@H:6]([OH:8])[CH3:7])[CH:2]=[CH2:3].F[C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([CH3:29])[CH:23]=1)=[N:14][CH:15]=[N:16]2>>[CH2:1]([N:4]([CH3:9])[CH2:5][C@@H:6]([CH3:7])[O:8][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([CH3:29])[CH:23]=1)=[N:14][CH:15]=[N:16]2)[CH:2]=[CH2:3]
Reactant: Cc1cc(Nc2ncnc3cccc(F)c23)ccc1O
Reactant: C=CCN(C)C[C@@H](C)O
Product: C=CCN(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Yield: 86 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using (2R)-1-[allyl(methyl)amino]propan-2-ol (obtained as described in Example 2.3, preparation of starting materials) and 4-[(5-fluoroquinazolin-4-yl)amino]-2-methylphenol (obtained as described in Example 3, preparation of starting materials) to give 4-[(5-{(1R)-2-[allyl(methyl)amino]-1-methylethoxy}quinazolin-4-yl)amino]-2-methylphenol as a brown oil in 86% yield; NMR spectrum (DMSO-d6) 1.43 (d, 3H), 2.15 (s, 3H), 2.18 (s, 3H), 2.54 (dd, 1H), 2.88 (dd, 1H), 3.00 (m, 2H), 4.92 (m, 1H), 5.01 (d, 1H), 5.11 (d, 1H), 5.62 (m, 1H), 6.77 (d, 1H), 7.16 (d, 1H), 7.26 (d, 1H), 7.35 (s, 1H), 7.38 (d, 1H), 7.66 (t, 1H), 8.37 (s, 1H), 9.17 (s, 1H), 10.16 (s, 1H); Mass spectrum MH+ 379.
Reaction SMILES: [BH4-].[Na+].[Si:3]([O:10][CH:11]([CH2:30][CH2:31][OH:32])[C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[O:22])=[CH:16][C:15]=1[F:29])=[O:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].C(=O)(O)[O-].[Na+]>CO>[Si:3]([O:10][CH:11]([CH2:30][CH2:31][OH:32])[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[O:22])=[CH:16][C:15]=1[F:29])[OH:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OC(CCO)C(=O)c1ccc(NC(=O)c2ccccn2)cc1F
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC(CCO)C(O)c1ccc(NC(=O)c2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
114 mg of sodium borohydride was added to a methanol (20 ml) solution of 860 mg of N-(4-(2-((t-butyl(dimethyl)silyl)oxy)-4-hydroxybutanoyl)-3-fluorophenyl)pyridine-2-carboxamide, with cooling with ice, and the reaction liquid was stirred at room temperature for 30 minutes. Aqueous saturated sodium bicarbonate solution was added to the reaction liquid, extracted with chloroform, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=100/1) to obtain the entitled compound as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]1([OH:33])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:37]>O1CCCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=1[C:20]1([O:33][CH3:37])[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(C(F)(F)F)cc2CO[Si](C)(C)C(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2ccc(C(F)(F)F)cc2CO[Si](C)(C)C(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h
Yield: 100.2 %

Procedure:
To a solution of tert-butyl 4-(2-((tert-butyldimethylsilyloxy)methyl)-4-(trifluoromethyl)phenyl)-4-hydroxypiperidine-1-carboxylate (526 mg; 1.07 mmol) in tetrahydrofuran (6 mL) at 0° C. was added sodium hydride (75 mg; 60% dispersion in mineral oil). The reaction was stirred for 10 minutes. Then iodomethane (0.10 mL; 1.61 mmol) was added. The reaction was stirred for 72 hours at room temperature. The reaction was quenched with water and 2N hydrochloric acid. The reaction was extracted with ethyl acetate. The organic layer was washed with water and brine. It was dried sodium sulfate and concentrated under reduced pressure. The residue was purified by 40 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-20% ethyl acetate in heptane) to give 540 mg (99.8% yield) of a colorless gum. MS (ES+): Calc: 503.6, Found: 445.4 (M−1BuH). 1H NMR (400 MHz, CDCl3) δ ppm 8.08 (s, 1H), 7.49, (dd, J=7.88, 8.30 Hz, 1H), 7.31 (d, J=8.30 Hz, 1H), 5.03 (s, 2H), 4.03 (bs, 2H), 3.16 (bs, 2H), 2.97 (s, 3H), 2.15 (d, J=12.86 Hz, 2H), 1.85 (bs, 2H), 1.48 (s, 9H), 0.98 (s, 9H), 0.14 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[O:13][C:14]2[CH:20]=[C:19]([C:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=3)[CH:18]=[CH:17][C:15]=2[N:16]=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[O:13][C:14]2[CH:20]=[C:19]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]3)[CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3nc(-c4ccc(S(C)(=O)=O)cc4F)oc3c2)CC1
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3nc(-c4ccc(S(C)(=O)=O)cc4F)oc3c2)CC1
Yield: 34.5 %

Procedure:
Following the general procedure-1 Tert-butyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}-5,6-dihydropyridine-1(2H)-carboxylate (35 mg) obtained from intermediate 41 (400 mg, 0.96 mmol) and tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (318 mg, 0.961 mmol). Tert-butyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}-5,6-dihydropyridine-1(2H)-carboxylate (50 mg, 0.11 mmol) dissolved in MeOH and added Pd/C (30 mg). This mixture was stirred in an auto clave under hydrogen atmosphere at 55 Psi for 12 h. Reaction mixture filtered through celite and washed the cetile with MeOH. Methanol was removed on rotavapour to obtain the crude. Crude was purified by combiflash using EtOAc and Petether (38:62) as eluent to obtain titled compound (18 mg) as an off-white solid. M.P.: 166.2-169.3° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.48-8.46 (m, 1H), 7.91-7.83 (m, 2H), 7.78 (d, J 8.3, 1H), 7.49 (s, 1H), 7.33-7.25 (m, 1H), 4.35-4.20 (m, 2H), 3.13 (s, 3H), 2.90-2.75 (m, 3H), 1.95-1.85 (m, 2H), 1.75-1.60 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[N:8][C:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2].O=S(Cl)[Cl:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:21])=[N:8][C:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(-c2cccnc2)nc1O
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of Compound 14c (5.05 g; 20.59 mmol) in DMF (70 mL) was added SOCl2 (3 mL; 41.23 mmol) dropwise at room temperature. The reaction was stirred at room temperature for 30 min, then poured into an ice water slurry of K2CO3 (3.41 g). The resultant solid (Compound 14d) was collected by filtration and dried. 1H NMR (300 MHz, CDCl3): δ 9.70 (s, 1H), 9.20 (s, 1H), 7.70-8.85 (m, 2H), 7.50 (dd, 1H), 4.50 (q, 2H), 1.45 (t, 3H); MS: m/z 264.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]#[N:25])=[CH:16]3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3]1.[OH-:29].[Na+].OO.O>CCO.CCOCC>[CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([NH2:25])=[O:29])=[CH:16]3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3]1
Reactant: [OH-]
Reactant: CC1(C)CC(Nc2nccc(-n3cc(C#N)c4ccccc43)n2)CC(C)(C)N1
Agent: OO
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CC1(C)CC(Nc2nccc(-n3cc(C(N)=O)c4ccccc43)n2)CC(C)(C)N1
Reaction time: 8 h
Yield: 57 %

Procedure:
1-[2-(2,2,6,6-Tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-1H-indole-3-carbonitrile (Example 208, 100 mg, 0.27 mmol) was dissolved in EtOH (3 ml), treated with 10N-NaOH (1 ml) and hydrogenperoxide (30%, 1 ml) and the resulting mixture was stirred vigorously overnight. After addition of water (50 ml) the mixture was extracted with ethylacetate. Crystallisation with ether finally gave 60 mg (0.15 mmol, 57%) of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:17]=[CH:18][C:19]([OH:21])=[O:20].[H][H]>[Pd].O1CCOCC1>[CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: COc1c(C=CC(=O)O)cccc1Oc1ccccc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: COc1c(CCC(=O)O)cccc1Oc1ccccc1Cl
Yield: 99.3 %

Procedure:
Palladium on carbon (500 mg) was added to a solution of 3-[2-methoxy-3-(2-chlorophenoxy)phenyl]acrylic acid (5.0 g) in dioxan (80 ml), and hydrogen gas (400 ml) was introduced into the mixture. After filtration, the filtrate was evaporated to give oily 3-[2-methoxy-3-(2-chlorophenoxy)phenyl]propionic acid (5.0 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[N:16]1[CH:20]=[CH:19][CH:18]=[N:17]1)([O-])=O>[Pd].CCO>[N:10]1([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([N:16]3[CH:20]=[CH:19][CH:18]=[N:17]3)[CH:6]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1-n1cccn1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCOCC2)cc1-n1cccn1

Procedure:
4-(4-Nitro-3-pyrazol-1-yl-phenyl)-morpholine was treated under standard hydrogenation conditions (H2, EtOH, 10% Pd/C) to yield desired 4-Morpholin-4-yl-2-pyrazol-1-yl-phenylamine as a crude oil, which was used for the subsequent reaction without further purification; TLC: 10:1 CH2Cl2:MeOH Rf 0.6, homogeneous (SM Rf 0.7); MS (m/e) 245.17 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:13]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCOCC1>[NH2:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Br:13])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: BrBr
Reactant: N#Cc1ccc([N+](=O)[O-])cc1N
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1cc(Br)c([N+](=O)[O-])cc1N
Temperature: 60 °C
Reaction time: 6 h
Yield: 36 %

Procedure:
2-Amino-4-nitrobenzonitrile (1.6 g, 9.81 mmol) is presented as an initial charge in 30 mL of dioxane and is mixed at 10° C. with bromine (0.56 mL, 11 mmol). This is followed by stirring at 60° C. for 6 hours. After cooling to room temperature, the batch is added to dilute sodium thiosulphate solution. After extraction of dichloromethane, the combined organic phases are dried over sodium sulphate to leave, after removal of the solvent and chromatographic purification (silica gel, n-hexane/ethyl acetate: 0→100% ethyl acetate), the product in 36% yield (820 mg).
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18](O)=[O:19])=[CH:16][C:3]1=2.B.O1CCCC1>O1CCCC1>[CH:16]1[C:3]2[CH2:2][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][O:5][C:4]=2[CH:13]=[CH:14][C:15]=1[CH2:17][CH2:18][OH:19]
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: B
Solvent: C1CCOC1
Product: OCCc1ccc2c(c1)Cc1ccccc1CO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 15.6 %

Procedure:
A solution of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid (100 g) in 450 ml dry tetrahydrofuran (THF) at -5° C. was treated with a 1M solution of borane-THF complex (373 ml in THF) under a nitrogen blanket. After stirring at ambient temperature for 72 hours, the reaction was quenched with methanol then diluted with water. Evaporation of the organic phase left an oily biphase which was basified with saturated sodium bicarbonate and extracted into dichloromethane. The organic phase was dried and evaporated to an oil which was purified by flash chromatography to give 14 g of 2-(6,11-dihydrodibenz[b,e]oxepin-2-yl)ethanol as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1)=[O:24]
Reactant: O=C(Cl)c1ccco1
Reactant: CN1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccco4)cc23)CC1
Yield: 8 %

Procedure:
Beginning with 1.13 gm (5.0 mMol) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 0.52 mL (5.0 mMol) 2-furoyl chloride, 0.129 gm (8.1%) of the title compound were recovered as a tan solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:3][CH2:2]1.[CH:13]1(CO)CCC[CH2:14]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:3][CH2:2][CH2:14][CH2:13]1
Reactant: Nc1cc(OCC2CC2)ncn1
Reactant: OCC1CCCC1
Product: Nc1cc(OCC2CCCC2)ncn1
Yield: 89 %

Procedure:
This was prepared in a manner analogous to 6-(cyclopropylmethoxy)pyrimidin-4-amine, where cyclopentylmethanol was used as the alcohol. 6-(cyclopentylmethoxy)pyrimidin-4-amine (0.266 g, 1.376 mmol, 89% yield) was obtained as a white solid. m/z (ESI) 194.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH2:10]2)=[CH:6][C:5]=1[NH2:13])([O-:3])=[O:2].[N+](C1C(N)=CC=C2C=1CCC2)([O-])=O.[CH3:27][C:28](OC(C)=O)=[O:29].NC1C=C2C(=CC=1)CCC2.[N+]([O-])([O-])=O.[K+]>O1CCOCC1.O>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH2:10]2)=[CH:6][C:5]=1[NH:13][C:28](=[O:29])[CH3:27])([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc2c(cc1[N+](=O)[O-])CCC2
Agent: Nc1ccc2c(c1)CCC2
Agent: Nc1ccc2c(c1[N+](=O)[O-])CCC2
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 20 °C
Reaction time: 16 h
Yield: 24 %

Procedure:
6-Nitro-5-indanamine (2) and 4-Nitro-5-indanamine (3). Ac2O (15.6 mL, 165 mmol) was added dropwise to a stirred solution of 5-aminoindan (1) (10 g, 75.1 mmol) in dioxane (40 mL) at 5° C. and the solution stirred at 20° C. for 16 h. The solution was diluted with water (100 mL) and the precipitate filtered, washed with water (2×10 mL) and dried. The solid was dissolved in cH2SO4 (100 mL) and cooled to 5° C. A solution of KNO3 (8.35 g, 82.6 mmol) in cH2SO4 (15 mL) was added dropwise and the solution stirred at 5° C. for 2 h, then at 20° C. for 2 h. The solution was poured into ice/water (500 mL) and the suspension stirred for 2 h. The precipitate was filtered, washed with water (2×20 mL) and dried. The solid was purified by chromatography, eluting with a gradient (20-40%) of EtOAc/pet. ether, to give (i) N-(6-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (3.97 g, 24%) as a colourless solid: mp (EtOAc/pet. ether) 105-108° C. [lit. (Schroeder, E., et al., European J. Med. Chem. 1982, 17, 35) mp 108-109° C.]; (ii) N-(4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (0.92 g, 5%) as a white solid: 1H NMR δ 9.51 (br s, 1H, NHCO), 8.28 (d, J=8.3 Hz, 1H, H-7), 7.41 (d, J=8.3 Hz, 1H, H-6), 3.25 (br t, J=7.5 Hz, 2H, H-1), 2.96 (br t, J=7.6 Hz, 2H, H-3), 2.22 (s, 3H, CH3), 2.07-2.13 (m, 2H, H-2); 13C NMR δ 164.1, 143.3, 142.1, 134.6, 131.9, 130.9, 117.3, 35.5, 32.1, 24.9; and (iii) N-(7-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (6.48 g, 39%) as a white solid: 1H NMR δ 7.94 (s, 1H, H-5), 7.89 (s, 1H, H-7), 7.44 (br s, 1H, NHCO), 3.36 (br t, J=7.5 Hz, 2H, H-3), 2.92 (br t, J=7.6 Hz, 2H, H-1), 2.20 (s, 3H, CH3), 2.09-2.18 (m, 2H, H-2).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.Cl.[F:21][C:22]1([F:26])[CH2:25][NH:24][CH2:23]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:24]2[CH2:25][C:22]([F:26])([F:21])[CH2:23]2)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: Clc1ccc(C2COCc3c(Cl)nc(Cl)nc32)cc1
Reactant: FC1(F)CNC1
Agent: Cl
Product: FC1(F)CN(c2nc(Cl)nc3c2COCC3c2ccc(Cl)cc2)C1
Yield: 67.9 %

Procedure:
2,4-dichloro-8-(4-chlorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation K) (500 mg, 1.584 mmol) and 3,3-Difluoroazetidine hydrochloride (308 mg, 2.377 mmol) were combined and purified as per Preparation Ha to give 2-chloro-8-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (400 mg, 1.075 mmol, 67.8% yield) as a white solid. LC-MS (M+H)+=372.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.22-7.34 (2 H, m), 7.12 (2 H, d, J=8.24 Hz), 4.63-4.85 (2 H, m), 4.46-4.64 (3 H, m), 4.04-4.17 (1 H, m), 3.91-4.04 (2 H, m).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:21][CH:20]=1>>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:12][CH2:13][N:14]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([CH:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:23][CH:24]=2)[CH2:15][CH2:16]1
Reactant: Fc1ccc(N2CCNCC2)c(F)c1
Reactant: CC(=O)NC(C)c1ccc(CCl)cc1
Agent: Cl
Product: CC(=O)NC(C)c1ccc(CN2CCN(c3ccc(F)cc3F)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(2,4-difluorophenyl)piperazine dihydrochloride instead of phenylpiperazine and N-(1-(4-chloromethylphenyl)ethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide, the title compound was obtained as white crystals, m.p.=109-111° C.