Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[O:22][CH:23]1[CH2:28][CH2:27]CCO1.BrCCCO>>[O:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[O:22][CH2:23][CH2:28][CH2:27][CH:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:8]
Reactant: C1CCC(OC2CCCCO2)OC1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: OCCCBr
Product: O=C(c1ccccc1)C(CCCOC1CCCCO1)c1ccccc1

Procedure:
The compound is prepared from 19.6 g of desoxybenzoin and 22.3 g of tetrahydropyran-2-yl ether-protected 3-bromopropanol according to the procedure described in Example 1(a).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:22][CH2:23][CH2:24]Cl)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]1([OH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:22][CH2:23][CH2:24][O:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCCCl)c3ccccc23)CC1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCCOc3ccccc3)c3ccccc23)CC1
Temperature: 100 °C
Yield: 83.1 %

Procedure:
A mixture of 3-tert-butyloxycarbonyl-6-(3-chloropropyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (213 mg), phenol (90 mg), DMF (2.0 mL), and K2CO3 (81 mg) was heated at 100° C. for 16 h, then allowed to cool to room temperature. The mixture was diluted with EtOAc (50 mL), then washed with water (3×10 mL). The organic layer was dried (MgSO4), filtered, and concentrated. Purification by flash chromatography (silica gel, 3:1 hexane:EtOAc) gave 205 mg of the title compound as an oil: 1H NMR (300 MHz, CDCl3) δ 7.45-7.55, 6.8-7.35, 4.33, 3.90, 3.55-3.75, 2.90-3.10, 2.12-2.28, 1.49; MS (ESI) m/z 421 (M+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[N:8]2.C([O-])([O-])=O.[K+].[K+].O1CCO[CH2:23][CH2:22]1>O>[CH2:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[N:8]2)[CH:22]=[CH2:23]
Reactant: COc1cnc2cccc(CBr)c2n1
Reactant: C1COCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=CCc1cccc2ncc(OC)nc12
Temperature: 110 °C
Reaction time: 48 h
Yield: 74 %

Procedure:
A suspension of 8-(bromomethyl)-2-methoxy-quinoxaline (8.0 g; prepared according to WO 2008/078305) and K2CO3 (8.74 g) in dioxane (154 mL) and water (20 mL) was degassed by bubbling N2 through for 20 min and treated with Pd(dppf)Cl2.DCM complex (1:1) (521 mg) and vinylboronic anhydride pyridine complex (5.12 g). The reaction was further stirred at 110° C. for 2 days and partitioned between water and ether. The org. phase was washed with water and brine, dried over MgSO4, concentrated under reduced pressure and purified by CC (Hex/EA 9:1 to 4:1), affording a yellow liquid (4.70 g, 74% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=2[NH:18][C:19]2[C:20]3[CH:28]=[C:27]([F:29])[C:26]([CH:30]([CH3:32])[CH3:31])=[N:25][C:21]=3[N:22]=[CH:23][N:24]=2)=[CH:4][CH:3]=1.[NH2:33][C:34]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([CH3:37])[CH2:35][OH:36]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:33][C:34]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([CH3:37])[CH2:35][OH:36])=[O:14])=[CH:11][C:10]=2[NH:18][C:19]2[C:20]3[CH:28]=[C:27]([F:29])[C:26]([CH:30]([CH3:31])[CH3:32])=[N:25][C:21]=3[N:22]=[CH:23][N:24]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1nc2ncnc(Nc3cc(C(=O)O)ccc3Sc3ccc(N)cc3)c2cc1F
Reactant: CC(N)(CO)c1ccccc1
Product: CC(C)c1nc2ncnc(Nc3cc(C(=O)NC(C)(CO)c4ccccc4)ccc3Sc3ccc(N)cc3)c2cc1F
Yield: 30 %

Procedure:
The title compound was prepared (yield 30%) by the procedure of Example 449I, substituting the product of Example 451D for the product of Example 449H. 1H-NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=7.0 Hz, 6H), 1.69 (s, 3H), 3.43-3.58 (m, 2H), 3.74 (dd, J=10.7, 5.9 Hz, 1H), 5.09 (t, J=5.9 Hz, 1H), 5.57 (br-s, 2H), 6.62 (d, J=8.5 Hz, 2H), 6.86 (d, J=8.5 Hz, 1H), 7.12 (d, J=8.5 Hz, 2H), 7.17 (br-t, J=7.0 Hz, 1H), 7.27 (t, J=7.0 Hz, 2H), 7.33 (br-d, J=7.0 Hz, 2H), 7.68 (dd, J=8.5, 1.5 Hz, 1H), 7.83 (d, J=1.5 Hz, 1H), 8.04 (s, 1H), 8.60 (s, 1H), 8.76 (d, J=10.3 Hz, 1H), 10.10 (s, 1H). MS ESI+ m/z: 583 (M+H), ESI− m/z: 581 (M−H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:23][CH:24]([CH3:27])[CH2:25][NH2:26].Cl>CN(C)C=O>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:26][CH2:25][CH:24]([CH3:27])[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: CC(C)CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 0 °C
Yield: 90 %

Procedure:
A mixture of 2,4-dichloro-3-nitroquinoline (100 g) and N,N-dimethylformamide (180 mL) was stirred, and triethylamine (42 g, 4 eq) was added dropwise, followed by dropwise addition of 2-methylpropylamine (21.5 g, 0.7 eq). The mixture was stirred at room temperature until the reaction was completed as determined by gas chromatography. Aqueous hydrochloric acid (250 mL, 4N) was added with stirring. The resulting mixture was stirred and cooled to about 0° C. to precipitate the product. The precipitate was filtered, washed with water, and dried at reduced pressure to afford the product 2-chloro-N-(2-methylpropyl)-3-nitro-4-quinolinamine in about 90% yield.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:18][CH2:19][CH:20]1[O:24][CH2:23][CH2:22][O:21]1.O>C(#N)C.C(OCC)(=O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:18][CH2:19][CH:20]2[O:24][CH2:23][CH2:22][O:21]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: NCC1OCCO1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)nc1NCC1OCCO1
Reaction time: 2 h

Procedure:
To a solution of 0.50 g of 2,6-dichloro-3-nitropyridine in 5 mL of acetonitrile, 0.43 g of potassium carbonate was added, thereto was added a solution of 0.24 mL of 2-aminomethyl-1,3-dioxolan in 3 mL of acetonitrile under cooling with ice, and the mixture was stirred for 2 hours under cooling with ice. Thereto was further added 80 μL of 2-aminomethyl-1,3-dioxolan, and the mixture was stirred for 2 hours under cooling with ice. Water and ethyl acetate were added thereto under cooling with ice, the organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of hexane:ethyl acetate=20:1 to obtain 0.44 g of 6-chloro-N-(1,3-dioxolan-2-ylmethyl)-3-nitropyridin-2-amine as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][C:5]([Cl:8])=[N:6][CH:7]=1.Br[CH2:11][C:12]1[S:13][CH:14]=[CH:15][C:16]=1[C:17]#[N:18]>>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH2:11][C:12]2[S:13][CH:14]=[CH:15][C:16]=2[C:17]#[N:18])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=c1[nH]c(Cl)ncc1Br
Reactant: N#Cc1ccsc1CBr
Product: N#Cc1ccsc1Cn1c(Cl)ncc(Br)c1=O
Yield: 58 %

Procedure:
The title compound was prepared in 58% yield from 2-chloro-5-bromo-3H-pyrimidin-4-one (Example 1A) and 2-bromomethyl-thiophene-3-carbonitrile according to the general procedure outlined for Example 1B. 1H NMR (400 MHz, CDCl3): δ 8.10 (s, 1H), 7.40 (d, 1H, J=5.6 Hz), 7.21 (d, 1H, J=5.6 Hz), 5.74 (s, 2H). MS (ES) [m+H] calc'd for C10H5N3OSBrCl, 330, 332; found 330, 332.
Reaction SMILES: [CH3:1][CH:2]([C:8](=[O:14])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH2:3][C:4](OC)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)(O)[O-].O>CCOCC.C(OCC)(=O)C>[CH3:1][CH:2]([CH:8]([OH:14])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH2:3][CH2:4][OH:5]
Reactant: COC(=O)CC(C)C(=O)CC=C(C)C
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)=CCC(O)C(C)CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 863.9 %

Procedure:
Methyl 3,7-dimethyl-4-oxo-6-octenoate (68 g, 34 mmole) in ether (10 ml) is added to a mixture of lithium aluminum hydride (1.3 g, 34 mmole) and ether (150 ml) at 0°. After the addition is complete the mixture is allowed to warm to room temperature and stirred for 1 hour, after which it is cooled to 0° and carefully added to a 5% aqueous sodim bicarbonate solution (50 ml). The resulting mixture is treated with water (100 ml) and ethyl acetate (300 ml). The organic phase is separated, dried (Na2SO4) and the solvent is removed in vacuo to give a colorless oil (50.6 g, 94%). This material shows one spot on TLC (silica gel 50% ethyl acetate in hexane) and is not further purified.
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[N:3]=1.Cl[CH2:27][C:28]1[CH:46]=[CH:45][C:31]([O:32][CH2:33][C:34]2[N:35]=[C:36]([C:40]3[O:41][CH:42]=[CH:43][CH:44]=3)[O:37][C:38]=2[CH3:39])=[C:30]([O:47][CH3:48])[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:41]1[CH:42]=[CH:43][CH:44]=[C:40]1[C:36]1[O:37][C:38]([CH3:39])=[C:34]([CH2:33][O:32][C:31]2[CH:45]=[CH:46][C:28]([CH2:27][O:1][C:2]3[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:15][CH:14]=4)[N:3]=3)=[CH:29][C:30]=2[O:47][CH3:48])[N:35]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of ethyl 3-hydroxy-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (3.00 g), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-2-(2-furyl)-5-methyloxazole (3.00 g), potassium carbonate (2.52 g), and N,N-dimethylformamide (30 ml) was stirred at 80° C. for 8 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (5.30 g, yield: 94%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 98–99° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:11]2[CH:10]=[C:9]([Se:12][C:13]#[C:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][N:16]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[CH:4][CH2:3]1.[OH-].[Na+]>>[CH3:1][C:2]1([CH3:33])[C:11]2[CH:10]=[C:9]([Se:12][C:13]#[C:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#C[Se]c2ccc3c(c2)C(C)(C)CC=C3c2ccc(C)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C2=CCC(C)(C)c3cc([Se]C#Cc4ccc(C(=O)O)cn4)ccc32)cc1

Procedure:
In a manner similar to that of Example 7d, by reacting 0.9 g (1.8 mmol) of ethyl 6-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-2-naphthylselanylethynyl)nicotinate with 0.36 g (9 mmol) of sodium hydroxide, a yellow solid is obtained (0.60 g; yield=71%; m.p.=171° C.).
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:6])[C:3]([NH2:5])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:6][C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:1])[CH2:3][NH2:5]
Reactant: CC(C)(Nc1ccccc1)C(N)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CN)Nc1ccccc1
Temperature: 0 °C

Procedure:
A solution of 2-Methyl-2-phenylamino-propionamide (1 eq) in dry THF (0.2 M) was added dropwise to a stirred ice-cooled suspension of LiAlH4(6 eq) in dry THF (1.2 M) under N2. Upon completion of the addition, the reaction mixture was refluxed for 24 h. The mixture was cooled to 0° C., quenched with water and filtered through Celite. The filtrate was concentrated under reduced pressure and partitioned between water and DCM. The organic phase was separated and washed with brine, then dried (Na2SO4) and concentrated under reduced pressure to yield KK1 as reddish oil which was used as such in the next step. MS (ES) C10H16N2 requires: 164, found: 165 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:23])[C:11]2[C:12](=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)[C:13](N)=[O:14])=[CH:5][CH:4]=1.[BH4-].[Na+].O>CO.O1CCCC1>[OH:14][CH:13]1[C:12]2[C:11](=[CH:19][CH:18]=[C:17]([N+:20]([O-:22])=[O:21])[CH:16]=2)[C:10](=[O:23])[N:9]1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2C(N)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(N2C(=O)c3ccc([N+](=O)[O-])cc3C2O)cc1
Yield: 96.3 %

Procedure:
N-(4-methoxyphenyl)-4-nitrophthalamide (12 g) was suspended in a mixture of methanol (80 ml) and tetrahydrofuran (80 ml) and, under ice-cooling and stirring, sodium borohydride (1.6 g) was added. Water (300 ml) was added to the mixture and crude crystals were collected by filtration to give a mixture (11 g) of 3-hydroxy-2-(4-methoxyphenyl)-5-nitroisoindolin-1-one and 3-hydroxy-2-(4-methoxyphenyl)-6-nitroisoindolin-1-one. The mixture (6.0 g) thus obtained and piperidinocarbonylmethylenetriphenylphosphoran (9.3 g) were dissolved in toluene (200 ml) under heating, and the solution was refluxed for 3 hours. After cooling, crystals separated were collected by filtration and recrystallized from toluene to give 2.2 g of 2-(4-methoxyphenyl)-6-nitro-3-piperidinocarbonylmethylisoindolin-1-one.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][OH:7].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][O:7][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][O:10]1
Reactant: C1=COCCC1
Reactant: CC(C)(CO)CCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(CCCBr)COC1CCCCO1
Yield: 90.4 %

Procedure:
According to the procedure for the preparation of 207d, 206a (78.0 g, 0.40 mol) was reacted with 3,4-dihydro-2H-pyran (41.5 g, 0.49 mol) and p-toluenesulfonic acid hydrate (0.42 g, 2.2 mmol) in CH2Cl2 (0.5 L) to yield 207a (101.0 g, 90%) as a pale-yellow oil, which was used without further purification. 1H NMR (CDCl3): δ 4.55 (t, 1H, J=2.9), 3.83 (m, 1H), 3.51 (m, 1H), 3.47 (d, 1H, J=9.0), 3.38 (t, 2H, J=6.8), 2.98 (d, 1H, J=9.0), 1.94-1.75 (m, 2H), 1.75-1.44 (m, 6H), 1.40 (t, 2H, J=8.5), 0.91 (s, 3H), 0.90 (s, 3H). 13C NMR (CDCl3): δ 99.01, 76.17, 61.85, 37.89, 34.66, 34.04, 30.62, 27.92, 25.60, 24.64, 24.56, 19.41. HRMS (LSIMS, nba): Calcd for C12H24BrO2 (MH+): 279.0960, found: 279.0955.
Reaction SMILES: [N:1]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[F:32][C:17]([F:16])([F:33])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26]([N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=3)[CH2:2][CH2:3]2)=[O:27])[N:19]=1
Reactant: N#Cc1ccc(N2CCCNCC2)nc1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: N#Cc1ccc(N2CCCN(C(=O)c3cccc(-c4noc(C(F)(F)F)n4)c3)CC2)nc1
Yield: 34 %

Procedure:
This compound was synthesized from 6-(1,4-diazepan-1-yl)nicotinonitrile and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (80 mg, yield 34%). 1H NMR (400 MHz, MeOD) δ 8.20-8.18 (m, 1H), 8.02 (m, 1H), 7.69-7.65 (m, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.55 (m, 1H), 7.38 (d, J=7.8 Hz, 1H), 6.78-6.76 (m, 1H), 4.01 (m, 1H), 3.93-3.90 (m, 2H), 3.83-3.79 (m, 2H), 3.75 (m, 2H), 3.48-3.46 (m, 1H), 2.07-2.02 (m, 2H). MS (ESI) m/z: Calculated for C21H17F3N6O2: 442.14. found: 443.2 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](O)=[O:6].ClC([N:18](C)C)=C(C)C.N>>[NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH2:18])=[O:6]
Reactant: Nc1c(Cl)ccc(C(=O)O)c1F
Reactant: CC(C)=C(Cl)N(C)C
Agent: N
Product: NC(=O)c1ccc(Cl)c(N)c1F
Yield: 69 %

Procedure:
The sub-title compound is prepared from 3-amino-4-chloro-2-fluoro-benzoic acid, (1-chloro-2-methyl-propenyl)-dimethyl-amine and conc NH3 in analogy to step Ac.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].CI.[C:15](=O)([O-])[O-].[K+].[K+]>>[N+:9]([C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[O:12][CH3:15])([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(Cl)cc(Cl)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COc1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Yield: 90.1 %

Procedure:
2-Nitro-4,6-dichloroanisole was prepared by the same procedure as described for Step 2 of Preparation 2a except using 2,4-dichloro-6-nitrophenol (52 g), methyl iodide (71 g), and potassium carbonate (41.4 g). Workup gave crude 2-nitro-4,6-dichloroanisole (50 g, 90%) which was used in the next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[N:11]1[N:15]=[C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]2=[N:12]1.[C:20](O)(=[O:24])[C:21]([CH3:23])=[CH2:22].C1(C=CC(O)=CC=1)O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:20](=[O:24])[C:21]([CH3:23])=[CH2:22])=[CH:4][C:3]=1[N:11]1[N:15]=[C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]2=[N:12]1
Reactant: C=C(C)C(=O)O
Reactant: OCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)C(=O)OCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Reaction time: 15.5 h

Procedure:
2-(2'-Hydroxy-5'-hydroxyethylphenyl)-2H-benzotriazole (150 g, 0.59 mol), methacrylic acid (55 ml, 0.65 mol), hydroquinone (2.4 g), p-toluenesulfonic acid monohydrate (3 g) and toluene (2 l) were placed in a 3 liter flask equipped with a Dean and Stark receiver. After 1.5 hours of refluxing the mixture, another 2.7 g of p-toluenesolfonic acid monohydrate was added and the refluxing was continued for another 15.5 hours. Approximately 10 ml of water was collected (theoretical: 10.6 g) and the yield of the desired compound was 93.7% as judged by a gas chromatography. Another 1 g of p-toluenesolfonic acid monohydrate was added and the reflusing was continued for another 3 hours. A yield of 95.6% was shown by a gas chromatography. After cooling the reaction mixture, it was washed with aqueous sodium hydrogen carbonate solution, water, 5% hydrochloric acid and water. The organic layer was dried with anhydrons magnesium sulfate and chromatographed through an alumina (Fisher, 80-200 mesh) column. After evaporation of the solvent, the residue was recrystallized from distilled methanol twice. Yield: 141.8 g (74%); Purity: >99.9% (G.C.). The IR and NMR data were consistent with the structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:16]([NH2:18])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27]Cl)[CH:20]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.[Na].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:16]([NH2:18])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][N:29]4[CH:33]=[CH:32][N:31]=[CH:30]4)[CH:20]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1c[nH]cn1
Reactant: COc1cccc(-c2cn(-c3cccc(OCCCl)c3)c3ncnc(N)c23)c1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.8 g of 5-(3-methoxyphenyl)-7-[3-(2-chloro-1-ethoxy)phenyl]-4-aminopyrrolo[2,3-d]-pyrimidine and 0.24 g of sodium imidazole are heated to 80° C. in 20 ml of DMF and stirred for 5 h. The mixture is then cooled to RT and treated with water, extracted 3 times with methylene chloride and concentrated. After chromatography on silica gel using methylene chloride/methanol 15:2 and crystallization from ether/methylene chloride, 5-(3-methoxy-phenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine having an m.p. of 138°-140° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][CH2:10][CH3:11])=[N:4][C:5]([F:8])=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+].[Br:17][C:18]1[CH:19]=[C:20]([C:25](Cl)=[O:26])[C:21]([Cl:24])=[N:22][CH:23]=1.O>CC#N>[Cl:24][C:21]1[C:20]([C:25]([NH:1][C:2]2[C:3]([NH:9][CH2:10][CH3:11])=[N:4][C:5]([F:8])=[CH:6][CH:7]=2)=[O:26])=[CH:19][C:18]([Br:17])=[CH:23][N:22]=1
Reactant: O=C(Cl)c1cc(Br)cnc1Cl
Reactant: CCNc1nc(F)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCNc1nc(F)ccc1NC(=O)c1cc(Br)cnc1Cl
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
To a cooled solution (4° C.) of 3-amino-2-(ethylamino)-6-fluoropyridine (31.0 g, 200 mmol) in MeCN (160 mL) was added solid NaHCO3 (50.4 g, 600 mmol). After 15 min, a solution of 5-bromo-2-chloro-3-pyridinecarbonyl chloride (1 equiv., 200 mmol) in MeCN (155 mL) was added. After 60 min at room temperature, the reaction mixture was poured into water (1.2 L) and stirred for 30 min. The resulting solid was filtered, dried under reduced pressure at 50° C. overnight. The title compound (73.7 g, 99% yield) was obtained as a black solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:21](=[O:22])[N:20]([C:23]3[CH:36]=[CH:35][C:26]([O:27][C:28]([CH3:34])([CH3:33])[C:29](OC)=[O:30])=[CH:25][CH:24]=3)[C:19]([CH3:37])=[N:18][C:17]=2[CH2:38][CH2:39][CH3:40])=[CH:11][CH:10]=1)#[N:2].C(OCC)(=O)C.O>O1CCCC1>[OH:30][CH2:29][C:28]([CH3:33])([CH3:34])[O:27][C:26]1[CH:35]=[CH:36][C:23]([N:20]2[C:21](=[O:22])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:17]([CH2:38][CH2:39][CH3:40])[N:18]=[C:19]2[CH3:37])=[CH:24][CH:25]=1
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)(C)C(=O)OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 2-(4-{5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl}phenoxy)-2-methylpropanoate (0.97 g) in tetrahydrofuran (10 mL) was added lithium tetrahydroboron (0.048 g), and the mixture was stirred at room temperature for 24 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.49 g, 53%).