Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[C:11](Cl)[N:10]=[CH:9][N:8]=2)=[CH:4][C:3]=1[F:16].[NH3:17]>O1CCCC1.CO>[NH2:17][C:11]1[CH:12]=[C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([NH2:1])=[C:3]([F:16])[CH:4]=2)[N:8]=[CH:9][N:10]=1
Reactant: N
Reactant: Nc1ccc(Oc2cc(Cl)ncn2)cc1F
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(Oc2ccc(N)c(F)c2)ncn1
Temperature: 25 °C
Yield: 35 %

Procedure:
After dissolving 4-(4-amino-3-fluorophenoxy)-6-chloropyrimidine (2.25 g) in tetrahydrofuran (25 ml) and a 7N ammonia solution in methanol (50 ml), the mixture was heated in a sealed tube for 3 days at 130° C. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate and 1N aqueous sodium hydroxide. The separated organic layer was washed with brine. The aqueous layer was then re-extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:3, then ethyl acetate) to provide the title compound (0.73 g, 35%) as a purple solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[NH2:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:23])[C:12]=2[C:11]([NH2:24])=[C:10]2[C:25](=[O:29])N[C:27](=[O:28])[C:9]=12.N>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:25](=[O:29])[C:10]2[C:9](=[C:8]([NH2:7])[C:21]3[C:20](=[O:22])[C:19]4[C:14]([C:13](=[O:23])[C:12]=3[C:11]=2[NH2:24])=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:27]1=[O:28]
Reactant: COCCCN
Reactant: Nc1c2c(=O)[nH]c(=O)c2c(N)c2c(=O)c3ccccc3c(=O)c12
Agent: N
Product: COCCCn1c(=O)c2c(N)c3c(=O)c4ccccc4c(=O)c3c(N)c2c1=O
Temperature: 40 °C
Yield: 130 %

Procedure:
225.2 g of 3-methoxypropylamine are charged to a 750 ml sulfonating flask and heated to 40° C. With stirring, 141.2 g of 1,4-diaminoanthraquinone-2,3-dicarboximide are added over 3 hours. The ensuing reaction is slightly exothermic, with evolution of NH3. The viscous suspension is stirred for another hour at 40°-45° C., then cooled to 20° C. and further stirred for one hour. The precipitated product is filtered with suction and washed with 300 ml of methanol and then with 300 ml of water, affording 226.6 g of N-(3-methoxypropyl)-1,4-diaminoanthraquinone-2,3-dicarboximide [dye of formula (3)]. After optional replenishment with fresh 3-methoxypropylamine, the mother liquor can be re-used for a new batch.
Reaction SMILES: [CH2:1]([C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:8][CH2:7][CH:6]1[OH:10])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:1]([C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:8][CH2:7][CH:6]1[O:10][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(C(=O)OCC)CCCC1O
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC1(C(=O)OCC)CCCC1OC(=O)c1ccccc1
Reaction time: 12 h
Yield: 93.7 %

Procedure:
10.7 grams of ethyl 1-n-butyl-2-hydroxy-cyclopentane carboxylate obtained in Example 16 were diluted with 60 ml of methylene chloride. At room temperature and with magnetic stirring, 6.108 ml of pyridine was slowly added, then 8.876 ml of benzoyl chloride was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then the procedure as described in Example 23 was followed, to give 19.06 g of brown liquid. The brown liquid was purified through column chromatography to give a liquid with a purity, measured by GC, of 96.03%. Yield: 93.7%. MS: 318(M+), 273(M+—OCH2CH3), 261(M+−CH2CH2CH2CH3), 245(M+—CO2CH2CH3), 213, 197(M+—C6H5CO2), 105(base), 77.
Reaction SMILES: [OH:1][CH:2]=[C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:15][CH3:16])[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[C:4]1=[O:17].[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[CH2:19]1[O:20][CH:2]([CH:3]2[CH2:12][CH2:11][C:10]3[C:5](=[C:6]([O:15][CH3:16])[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=3)[C:4]2=[O:17])[O:1][CH2:18]1
Reactant: COc1cc2c(c(OC)c1)C(=O)C(=CO)CC2
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1cc2c(c(OC)c1)C(=O)C(C1OCCO1)CC2

Procedure:
A solution containing 5.73 g. of 2-hydroxymethylene-6,8-dimethoxy-1-tetralone, 2.23 g. of ethylene glycol and 100 mg. of p-toluenesulfonic acid in 25 ml. of benzene was heated at reflux two hours under a Dean-Stark water separator. The mixture was filtered, the filtrate was washed with saturated aqueous solutions of sodium bicarbonate and sodium chloride, dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo to give 1,2,3,4-tetrahydro-6,8-dimethoxy-1-oxo-2-naphthaldehyde ethylene acetal which was converted directly to 1,2,3,4-tetrahydro-1-hydroxy-6,8-dimethoxy-2-naphthaldehyde ethylene acetal as described hereinabove in Example 155.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[N:21]([C:22]=1[C:23](O)=[O:24])[CH:20]=[CH:19][S:18]2.[CH3:28][C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH3:26][C:2]([CH3:1])([CH3:27])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[N:21]([C:22]=1[C:23]([NH:34][C:31]1[S:32][CH:33]=[C:29]([CH3:28])[N:30]=1)=[O:24])[CH:20]=[CH:19][S:18]2
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC(C)(C)C
Reactant: Cc1csc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C)cs2)c1OCC(C)(C)C

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 3 (250 mg, 0.646 mmol) with 4-methyl-1,3-thiazol-2-amine (82 mg, 0.711 mmol) in the presence of EDCI hydrochloride (247 mg, 1.292 mmol) and DMAP (36.33 mg, 0.323 mmol) in a mixture of DCM and DMF (4:1, 10 mL) to give 110 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.06 (s, 9H), 2.28 (s, 3H), 3.57 (s, 2H), 3.80 (s, 3H), 6.62 (s, 1H), 6.98 (d, J=7.8 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 7.36-7.40 (m, 2H), 7.88 (d, J=16.2 Hz, 1H), 7.98-8.20 (br m, 1H), 8.55 (br m, 1H), 12.89 (br s, 1H); ESI-MS (m/z) 483.33 (MH)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Br)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27].O.C(=O)([O-])[O-].[Na+].[Na+]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:31]3[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[CH:29][CH:30]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2ncccc2Br)cc1)c1nc2ccccc2[nH]1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(-c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)cc1
Temperature: 135 °C

Procedure:
A glass microwave reaction vessel was charged with (1H-benzo[d]imidazol-2-yl)(4-(3-bromopyridin-2-yloxy)phenyl)methanone (0.1427 g, 0.36 mmol), 4-cyanophenylboronic acid (0.0760 g, 0.43 mmol), trans-dichlorobis(triphenyl-phosphine)palladium(ii) (0.0314 g, 0.029 mmol), and sodium carbonate monohydrate (0.13 mL, 1.8 mmol) in 1,2-dimethoxymethane (3 mL) and water (1 mL). The reaction mixture was stirred and heated in a Biotage™ Initiator™ microwave reactor at 135° C. for 10 min. The solvent was evaporated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ pre-packed silica gel column (25M), eluting with a gradient of 10% to 80% ethyl acetate in hexane, to provide 4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)benzonitrile. MS (ESI, pos. ion) m/z: 417.5 (M+1). IC50 (uM) +++++.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][OH:20])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:21][O:22]C1C=CC(CCl)=CC=1.O>C1(C)C=CC=CC=1>[CH3:21][O:22][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH2:19][OH:20])=[N:11]2)=[CH:9][CH:8]=1
Reactant: COc1ccc(CCl)cc1
Reactant: OCc1nn(Cc2ccccc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2nc(CO)c3ccccc32)cc1
Temperature: 25 °C
Yield: 27.2 %

Procedure:
To a suspension of 60% NaH (2.7 g; 0.07 mol) in toluene (200 ml) was added 1-benzyl-3-hydroxymethylindazole (10 g; 0.07 mol). The mixture was brought to boiling point and left stirring at reflux for 1 hour. 4-Methoxybenzyl chloride (14 g; 0.09 mol) was then added. The mixture was then stirred at reflux for 4 hours. The reaction was completed by cooling the mixture to room temperature and adding water (50 ml). The organic phase was separated out and washed, respectively, with 2N HCl (50 ml) and water (5×50 ml). The solvent was evaporated off under reduced pressure. The crude residue thus obtained was purified by flash chromatography on silica gel, using as eluent a 3/2 hexane/ethyl acetate mixture. The product obtained was crystallized from a 5/1 hexane/ethyl acetate mixture to give 5.1 g of [1-(4-methoxybenzyl)-1H-indazol-3-yl]methanol with a melting point of 95°-97° C.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([CH2:10][O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N-:13]=[N+:14]=[N-:15].[Na+].Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:12][O:11][CH2:10][C:8]1[N:9]=[C:2]([NH2:1])[C:3]([C:4]2[N:13]=[N:14][NH:15][N:5]=2)=[CH:6][CH:7]=1
Reactant: COCc1ccc(C#N)c(N)n1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COCc1ccc(-c2nn[nH]n2)c(N)n1
Temperature: 160 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
2-Amino-6-methoxymethyl-nicotinonitrile (0.20 g) described in Manufacturing Example 6-2, sodium azide (0.40 g), triethylamine hydrochloride (1.7 g), and NMP (25 mL) were stirred for 2 hours at 160° C. The reaction solution was directly purified by silica gel chromatography (ethyl acetate, then ethyl acetate:methanol:concentrated aqueous ammonia=6:2:1). The organic layer thus obtained was concentrated and purified by silica gel chromatography (ethyl acetate:methanol=4:1) to obtain the titled compound (170 mg).
Reaction SMILES: C([Li])CCC.[CH2:6]1[C:19]2[C:10](=[N:11][C:12]3[C:17]([C:18]=2[NH2:20])=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][CH2:8][CH2:7]1.Cl[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:23].O>O1CCCC1>[CH2:16]1[C:17]2[C:12](=[N:11][C:10]3[C:19]([C:18]=2[NH:20][C:22](=[O:23])[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:13][CH2:14][CH2:15]1
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Reactant: CCCCCCCCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCOC(=O)Nc1c2c(nc3ccccc13)CCCC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 56.3 %

Procedure:
n Butyllithium, 0.033 mol, is added to a suspension of 6.5g (0.033 mol) of 1,2,3,4-tetra -hydro-9-acridinamine (Petrow, V., Journal of the Chemical Society, pages 634 to 637 (1947)) in 200 ml of tetrahydrofuran at 0° C. The mixture is stirred at 0° C. for 20 minutes, the cooling bath removed and 6.36 g (0.033 mol) of octyl chloroformate added and the solution stirred over the weekend. Water, 200 ml, is added and the mixture extracted with ethyl acetate. The ethyl acetate layer is separated and evaporated to afford a yellow oil. Chromatography (elution with isopropanol-chloroform (5:95)) affords 6.59 g of octyl (1,2,3,4-tetrahydro-9-acridinyl)carbamate, as a yelIow solid; mp 96-99° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH:14]=O)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[NH2:23][C:24]1[C:33]([F:34])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28]([CH3:35])=[N:29]2.C([BH3-])#N.[Na+]>>[F:34][C:33]1[C:24]([NH:23][CH2:14][C:13]([OH:20])([C:16]([F:17])([F:19])[F:18])[CH2:12][C:11]([C:4]2[C:5]3[O:9][CH2:8][CH2:7][C:6]=3[CH:10]=[C:2]([F:1])[CH:3]=2)([CH3:21])[CH3:22])=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[C:28]([CH3:35])[CH:27]=[CH:26]2
Reactant: Cc1ccc2c(N)c(F)ccc2n1
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1cc(F)cc2c1OCC2
Agent: [BH3-]C#N
Agent: [Na+]
Product: Cc1ccc2c(NCC(O)(CC(C)(C)c3cc(F)cc4c3OCC4)C(F)(F)F)c(F)ccc2n1

Procedure:
Analogously to Example 1, the corresponding imine is produced starting from 250 mg of 4-(2,3-dihydro-5-fluoro-7-benzofuranyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and 138 mg of 5-amino-6-fluoro-2-methylquinoline. After reaction with sodium cyanoborohydride, the title compound is obtained.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[CH2:36][CH:37]1[CH2:39][CH2:38]1>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][N:24]([CH2:36][CH:37]4[CH2:39][CH2:38]4)[CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: BrCC1CC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(CC3CC3)CC2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=540.3 (M+H+), was prepared in accordance with the general method of example 35 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone and bromomethyl cyclopropane.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:21]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]1.C(Br)(Br)(Br)[Br:34]>C1COCC1>[Br:34][CH:21]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Br)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Triphenylphosphine (727 mg, 2.77 mmol) was added to a stirred solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (173 mg, 0.924 mmol) and carbon tetrabromide (919 mg, 2.77 mmol) in THF (3.00 mL) at 0° C., and the resulting mixture was allowed to warm slowly to rt. After 20 h, the reaction was filtered and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 10%-40% EtOAc/hexanes as eluent) afforded the title compound i-5a m/z (ES) 250 (MH)+. 1H NMR (500 MHz, CDCl3): δ 4.49 (m, 1H), 3.81 (m, 2H), 3.63 (m, 1H), 3.53 (m, 1H), 2.33 (m, 1H), 2.26 (m, 1H), 1.49 (s, 9H).
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH3:3].Br[CH2:19][CH2:20][CH2:21][OH:22].C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[C:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:16][CH2:17]2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: OCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1cccc(C2CCN(CCCO)CC2)c1
Yield: 83.5 %

Procedure:
5.3 g (20.8 mmol) of 4-(3-acetylaminophenyl)piperidine hydrochloride was dissolved in 50 ml of N,N-dimethylformamide, and then 3.8 g (27.0 mmol) of 3-bromo-1-propanol and 8.6 g (62 mmol) of K2CO3 were added to the resulting solution, followed by treating the mixture at 60° C. for 5 hours. The reaction mixture was combined with 150 ml of water and extracted with ethylacetate (100 ml×5), and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (10% methanol/CH2Cl2) to obtain 4.8 g (yield 85%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:6]=2[CH:19]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:40][CH3:41])[C:24]([Cl:42])=[CH:23][N:22]=1>>[Cl:42][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:29]=2[O:40][CH3:41])=[N:26][C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:6]=3[CH:19]=2)=[N:22][CH:23]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CC(C)CN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)N(CC(C)C)C(=O)CCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-isobutyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine to yield a colorless solid (9%). LCMS: m/z=579.59 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.22 (d, 1H, J=8.8 Hz), 8.05 (d, 1H, J=1.0 Hz), 7.67 (bs, 1H), 7.62 (bs, 1H), 7.22 (m, 3H), 6.55 (d, 1H, J=1.5 Hz), 6.48 (dd, 1H, J=8.8, 1.5 Hz), 3.93 (s, 3H), 3.90 (m, 4H), 3.16 (m, 4H), 2.36 (m, 5H), 2.05 (m, 2H), 1.35 (s, 6H), 0.97 (d, 6H, J=6.6 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[C:3]([O:5][CH2:6][N:7]1[C:15](=[O:16])[C:14]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH:23]=[O:24])[CH:12]=[N:11][C:10]=2[N:9]([CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:8]1=[O:33])=[O:4].[Cl:36]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Cl:36][C:12]1[N:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH:23]=[O:24])[C:14]2[C:15](=[O:16])[N:7]([CH2:6][O:5][C:3](=[O:4])[C:2]([CH3:35])([CH3:34])[CH3:1])[C:8](=[O:33])[N:9]([CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:29])([CH3:31])[CH3:30])[C:10]=2[N:11]=1
Reactant: CC(C)(C)C(=O)OCn1c(=O)c2c(ncn2-c2ccccc2C=O)n(COC(=O)C(C)(C)C)c1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1c(=O)c2c(nc(Cl)n2-c2ccccc2C=O)n(COC(=O)C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
2,2-Dimethylpropionic acid [1-(2,2-dimethylpropionyloxymethyl)-7-(2-formylphenyl)-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]methyl ester (2.50 g) and N-chlorosuccinimide (896 mg) were dissolved in N,N-dimethylformamide (25 ml), and the mixture was stirred at room temperature for 8 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 2.0 g of the title compound from the elution fraction of hexane-ethyl acetate (2:1).
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][O:6][C:5]2[CH:9]=[C:10]([F:14])[C:11]([Br:13])=[CH:12][C:4]=2[C:3]1=O.[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[S:18])[NH2:17]>C(O)C.CN1C(=O)CCC1>[CH2:22]([O:21][C:19]([C:16]1[S:18][C:2]2[CH2:8][CH2:7][O:6][C:5]3[CH:9]=[C:10]([F:14])[C:11]([Br:13])=[CH:12][C:4]=3[C:3]=2[N:17]=1)=[O:20])[CH3:23]
Reactant: O=C1c2cc(Br)c(F)cc2OCCC1Br
Reactant: CCOC(=O)C(N)=S
Solvent: CN1CCCC1=O
Solvent: CCO
Product: CCOC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Temperature: 80 °C
Reaction time: 3 h
Yield: 25.3 %

Procedure:
Into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 4,7-Dibromo-8-fluoro-3,4-dihydro-2H-benzo[b]oxepin-5-one (1400 g, 4.14 mol, 1.00 equiv), NMP (0 mg), and ethyl carbamothioylformate (554 g, 4.16 mol, 1.00 equiv). The resulting solution was stirred at 80° C. for 3 h, cooled to 25° C. and diluted with 6 L of ethanol. The solids were collected by filtration, washed with 3×1 L of ethanol and dried to afford 390 g (25%) of 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester
Reaction SMILES: Cl[C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][S:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CN(C=O)C>[O:16]1[CH2:17][CH2:18][N:13]([C:2]2[C:6]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)=[N:5][S:4][N:3]=2)[CH2:14][CH2:15]1
Reactant: Clc1nsnc1-c1cccnc1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: c1cncc(-c2nsnc2N2CCOCC2)c1

Procedure:
A solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (0.59 g, 3 mmol) and morpholine (1.3 g, 15 mmol) in DMF (5 ml) was heated at 100° C. for 3 h. After evaporation water was added to the residue and extracted with ether. The combined and dried organic phases were evaporated and the residue purified by column chromatography (SiOa, eluent:ethyl acetate/methylene chloride (1:1)). Yield: 0.68 g (91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1.Br[CH2:11][C:12](=O)[CH3:13].N12CCCN=C1CCCCC2>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]2[C:5]([CH:4]=1)=[CH:9][C:12]([CH3:13])=[CH:11]2
Reactant: CC(=O)CBr
Reactant: COc1ccnc(C)c1
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccn2cc(C)cc2c1
Temperature: 0 °C
Yield: 31 %

Procedure:
4-Methoxy-2-methylpyridine (0.123 g, 1 mmol) and bromoacetone (0.16 mL, 1 mmol) were heated at 95° C. under N2 for 2 h. 1,8-Diazabicyclo-[5.4.0]-undec-7-ene (0.34 mL, 2.2 mmol) in benzene (10 mL) was added. The mixture was then refluxed under N2 for 1 h, poured into ice water, and then extracted with EtOAc. The combined organic layers were washed with water and dried. After the solvent was removed in vacuo, the residue was purified on a silica gel column eluting with EtOAc:Hexane (1:9) and EtOAc to give 7-methoxy-2-methylindolizine (0.050 g, 31%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([F:12])([F:11])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>ClCCl>[Br:13][C:3]1[CH:4]=[CH:5][C:6]2[O:7][C:8]([F:12])([F:11])[O:9][C:10]=2[C:2]=1[NH2:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc2c1OC(F)(F)O2
Solvent: ClCCl
Product: Nc1c(Br)ccc2c1OC(F)(F)O2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a stirred solution of 4-amino-2,2-diflouro-1,3-benzodioxole (2.5 g, 14.4 mmol) in dichloromethane at 0° C. was added N-bromosuccinimide (2.7 g, 15.2 mmol) portion wise. The solution was stirred at 0° C. for 30 min, then at room temperature for 1 h. The reaction mixture was quenched with 1M sodium thiosulfate solution and diluted with deionized water, extracted with dichloromethane (2×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-20% ethyl acetate in hexanes) to recover starting material 1 g and afford 5-bromo-4-amino-2,2-diflouro-1,3-benzodioxole as colorless oil (2.33 g, 9.25 mmol, 64%). MS: (ES) m/z calculated for C7H4BrF2NO [M+H]+252.0. found 252.