Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[C:5]([C:25](=[O:44])[NH:26][C:27]1[CH:32]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:30]=[C:29]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:28]=1[O:42][CH3:43])[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:8][CH:7]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:33]([C:31]1[CH:32]=[C:27]([N:26]2[C:3](=[O:2])[CH:4]=[C:5]([C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]([O:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:8][CH:7]=3)[C:25]2=[O:44])[C:28]([O:42][CH3:43])=[C:29]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:30]=1)([CH3:34])([CH3:35])[CH3:36]
Reactant: COC(=O)C=C(C(=O)Nc1cc(C(C)(C)C)cc(NS(C)(=O)=O)c1OC)c1ccc(OCCN2CCOCC2)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1c(NS(C)(=O)=O)cc(C(C)(C)C)cc1N1C(=O)C=C(c2ccc(OCCN3CCOCC3)c3ccccc23)C1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
In a 40 mL scintillation vial was placed 3-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-acrylic acid methyl ester 51 (25 mg, 0.04 mmol), DIEA (13.6 mL, 0.08 mmol), and 5 mL THF. The reaction was heated to 80° C., stirring for 16 hours. The resulting reaction mixture was concentrated under vacuum and the crude residue purified by reverse phase preparative LC-MS to afford (10.2 mg, 39%) of the desired compound. Calculated mass=607. Observed mass=608.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.ClC1C(Cl)=CC(C(F)(F)F)=CN=1.C([O-:30])(C)(C)C.[K+].C([O-])(C)(C)C.[Na+].[OH-:38].[K+]>CS(C)=O.[N+](C)([O-])=O>[Cl:9][C:8]1[C:3]([CH2:2][N+:1]([O-:30])=[O:38])=[N:4][CH:5]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:7]=1
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Reactant: CC(C)(C)[O-]
Reactant: [OH-]
Agent: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C[N+](=O)[O-]
Product: O=[N+]([O-])Cc1ncc(C(F)(F)F)cc1Cl

Procedure:
The process according to the present invention is particularly suitable for the preparation of 2-aminomethyl-3-chloro-5-trifluoromethylpyridine, by reaction of in the first step 2,3-dichloro-5-trifluoromethylpyridine with nitromethane in the presence of potassium tert-butanolate, sodium tert-butanolate, or potassium hydroxide in DMSO as diluent to give 3-chloro-2-nitromethyl-5-trifluoromethylpyridine, which in the second step is hydrogenated in hydrochloric acid using palladium on carbon as catalyst to yield 3-chloro-2-aminomethyl-5-trifluoromethylpyridine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][N:12]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:22][CH:21]=4)[C:16]([C:17]([NH2:19])=[O:18])=[C:11]3[NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:35][CH2:36][N:37]([CH3:39])[CH3:38]>>[CH3:38][N:37]([CH3:39])[CH2:36][CH2:35][O:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][N:12]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:22][CH:21]=4)[C:16]([C:17]([NH2:19])=[O:18])=[C:11]3[NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(c1cccc(O)c1)C2
Reactant: CN(C)CCCl
Agent: Cl
Product: CN(C)CCOc1cccc(C2CNc3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn3C2)c1

Procedure:
The desired product was prepared from 6-(3-hydroxyphenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and 2-chloro-N,N-dimethylethanamine hydrochloride using the procedure similar to step 7 for compound 9. 1H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J=8.4 Hz, 2H), 7.46-7.38 (m, 2H), 7.29 (t, J=7.6 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H), 7.10-7.05 (m, 4H), 6.98-6.96 (m, 2H), 6.90-6.88 (m, 1H), 6.81 (d, J=2.4 Hz, 1H), 4.25-4.20 (m, 1H), 4.16-4.11 (m, 3H), 3.50-3.47 (m, 1H), 3.43-3.38 (m, 2H), 2.96-2.84 (m, 2H) and 2.43 (s, 6H). MS (ESI) m/e [M+1]+ 497.9.
Reaction SMILES: C[O:2][CH:3]([O:23]C)[CH:4]([CH3:22])[N:5]1[C:9]2[CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.S(=O)(=O)(O)O>C(O)(=O)C.O>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[N:6][N:5]([CH:4]([CH3:22])[C:3]([OH:23])=[O:2])[C:9]=2[CH:10]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(OC)C(C)n1nnc2ccc(OCc3ccccc3)cc21
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(C(=O)O)n1nnc2ccc(OCc3ccccc3)cc21
Temperature: 25 °C

Procedure:
A solution of 6-(benzyloxy)-α-methyl-1H-benzotriazole-1-acetaldehyde dimethyl acetal (95 g, 0.272 mole) and concentrated sulfuric acid (20 ml) in acetic acid and water is heated at 72° C. for 20 hours, cooled to room temperature and concentrated in vacuo. The concentrated solution is diluted with acetone and water and treated with KMnO4 (140 g) in portions over a three hour period at 18°-30° C. with stirring.
Reaction SMILES: O.[OH-].[Li+].C([O:6][P:7]([CH2:14][CH2:15][CH2:16][NH2:17])([CH:9]1[CH2:13][CH2:12][CH2:11][O:10]1)=[O:8])C>O.C(O)C>[NH2:17][CH2:16][CH2:15][CH2:14][P:7]([CH:9]1[CH2:13][CH2:12][CH2:11][O:10]1)(=[O:6])[OH:8]
Reactant: CCOP(=O)(CCCN)C1CCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NCCCP(=O)(O)C1CCCO1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 0.57 g of lithium hydroxide monohydrate in 10 ml of water is added a solution of 2.0 g of ethyl-3-aminopropyl(tetrahydrofuran-2-yl)phosphinate in 20 ml of ethanol. A slight exothermic reaction ensues and the reaction mixture becomes turbid. A further 5 ml of water is added and the then clear solution stirred for 3 days at room temperature. After this time, the reaction mixture is concentrated in vacuo at 55°. The residue is re-dissolved in water and washed with 3×10 ml of dichloromethane. The aqueous layer is again evaporated to dryness and the residue dissolved in 10 ml of water and treated with 0.65 ml of 85% phosphoric acid in 2 ml of water. After stirring overnight, the solid is removed by filtration. Evaporation of the filtrate and crystallisation of the residue from methanol/ether affords 3-aminopropyl(tetrahydrofuran-2-yl)phosphinic acid, m.p. 222°-223° (dec.), as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(Cl)=[S:27]>O1CCCC1>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:9]=2)=[CH:4][CH:3]=1)=[C:26]=[S:27]
Reactant: Nc1ccc(-c2nc(-c3ccccn3)no2)cc1
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=C=Nc1ccc(-c2nc(-c3ccccn3)no2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 53.3 %

Procedure:
To a solution of 1.09 g of 5-(4-aminophenyl)-3-(2-pyridyl)-1,2,4-oxadiazole in 200 ml of dry tetrahydrofuran containing 0.42 g of triethylamine, 0.50 g of thiophosgene is added and the mixture stirred at room temperature for 6 hours. After filtration, the solution is evaporated in vacuo to give the crude product. It is crystallized from petroleum ether to give 0.65 g (54%) of the title product, m.p. 145°-146°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]([CH3:8])=[N:6][CH:7]=1.[Se](=O)=[O:15]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]([CH:8]=[O:15])=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cc(Br)cnc1C
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(Br)cnc1C=O
Temperature: 180 °C

Procedure:
To each of 106 separate 20-mL microwave vials, add: ethyl 5-bromo-2-methylpyridine-3-carboxylate (5 g, 20.48 mmol, 1.0 equiv), selenium dioxide (2.98 g, 26.63 mmol, 1.3 equiv), and 1,4-dioxane (13 mL). Heat the vessels to 180° C. for 20 min with microwave irradiation. Combine the contents of the reaction vessels; filter through a pad of silica gel (2 kg); and rinse the pad with DCM (3 L). Concentrate the combined filtrates under reduced pressure. Split the material into two equally-sized batches, and pass each through a pad of silica gel (2 kg) eluting with DCM. Concentrate the filtrate under reduced pressure to furnish the title compound as a yellow or pale orange solid (473 g, 93.2% yield). MS (m/z) (79Br/81Br) 258/260 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([C:15]1[S:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:17][C:16]=1[OH:26])[CH3:14])[CH:7]=[CH:6]2.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([C:15]1[S:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:17][C:16]=1[O:26][C:27](=[O:29])[CH3:28])[CH3:14])[CH:7]=[CH:6]2
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2cc(C(C)c3sc(-c4ccccc4)nc3O)ccc2c1
Solvent: c1ccncc1
Product: COc1ccc2cc(C(C)c3sc(-c4ccccc4)nc3OC(C)=O)ccc2c1

Procedure:
The desired compound is prepared by treatment of the product of Example 5 with acetic anhydride and pyridine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([OH:13])=[O:12])[C:2]1=2.[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@@H:23](O)[CH2:22]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:11]([O:13][C@@H:23]3[CH:24]4[CH2:27][CH2:28][N:21]([CH2:26][CH2:25]4)[CH2:22]3)=[O:12])[C:2]1=2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1ccccc1)c1cccc2ccsc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1cccc2ccsc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.9 %

Procedure:
A mixture of 2-(benzo[b]thiophen-7-yl)-2-(phenylamino)acetic acid (I26) (303 mg, 1.07 mmol), (R)-quinuclidin-3-ol (136 mg, 1.07 mmol), DCC (221 mg, 1.07 mmol) and HOBT (164 mg, 1.07 mmol) in THF (20 ml) was stirred at r.t. for three days. THF was evaporated, and the crude product was taken up with EtOAc and washed twice with 2M K2CO3, and then with brine. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (EtOAc/MeOH=9/1 to EtOAc/MeOH=9/1+0.5% NH4OH) to obtain (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-7-yl)-2-(phenylamino)acetate (180 mg, 42.9% yield).
Reaction SMILES: B(F)(F)F.CC[O:7]CC.[Br:10][C:11]1[C:20]2[C:19]([CH3:21])=[CH:18][CH2:17][CH2:16][C:15]=2[CH:14]=[CH:13][C:12]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])(=[O:25])=[O:24]>C1COCC1>[Br:10][C:11]1[C:20]2[C@H:19]([CH3:21])[C@@H:18]([OH:7])[CH2:17][CH2:16][C:15]=2[CH:14]=[CH:13][C:12]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])(=[O:25])=[O:24]
Reactant: CCOCC
Reactant: CC1=CCCc2ccc(NS(=O)(=O)c3ccccc3F)c(Br)c21
Agent: FB(F)F
Solvent: C1CCOC1
Product: C[C@H]1c2c(ccc(NS(=O)(=O)c3ccccc3F)c2Br)CC[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57 %

Procedure:
A mixture of R-[N,N′-bis(monoisopinocampheylborane)-N,N,N′,N′-tetramethylethylenediamine] (1.25 g, 3.0 mmol) in THF (5 mL) was treated with boron trifluoride etherate, stirred at room temperature for 1.5 hours, and filtered. The filter cake was washed with THF (2.5 mL). Half of the solution containing the free isopinocamphenylborane (1.5 mmol) was cooled to −25° C., treated with a solution of Example 275D (500 mg, 1.25 mmol) in THF (3 mL), stirred at −20° C. for 48 hours, warmed to 0° C., and quenched with methanol (0.5 mL). The solution was treated with 3M NaOH (1.1 mL), followed by 30% H2O2 (0.9 mL) dropwise, stirred for 1 hour at 50° C., cooled to room temperature, extracted with diethyl ether, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30% acetone/hexanes to give 300 mg (57% yield). MS (ESI) m/e 412 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.02 (s, 1H), 7.69 (m, 1H), 7.63 (dt, 1H), 7.42 (m, 1H), 7.30 (dt, 1H), 7.0 (d, 1H), 6.92 (d, 1H), 4.73 (d, 1H), 3.85 (m, 1H), 2.95 (m, 1H), 2.82 (m, 1H), 2.6 (m, 1H), 1.81 (m, 1H), 1.69 (m, 1H), 0.98 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[NH:5][C:4](=[O:11])[CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CN(C)C(=O)C>[CH3:14][N:15]([CH3:17])[CH:16]=[N:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[NH:5][C:4](=[O:11])[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: CCn1c(N)cc(=O)[nH]c1=O
Solvent: CC(=O)N(C)C
Product: CCn1c(N=CN(C)C)cc(=O)[nH]c1=O
Temperature: 40 °C

Procedure:
A suspension of 6-amino-1-ethyl-1,3-dihydropyrimidine-2,4-dione (0.77 g, 5 mmol) in anhydrous N,N-dimethylacetamide (25 ml) and N,N-dimethylformamide dimethylacetal (2.7 ml, 20 mmol) and was warmed at 40° C. for 90 minutes. Solvent was then removed under reduced pressure, and the residue triturated with ethanol, filtered, and washed with ethanol, to provide 6-[2-(dimethylamino)-1-azavinyl]-1-ethyl-1,3-dihydropyrimidine-2,4-dione, a compound of formula (6). 1H-NMR (DMSO-d6) δ 10.62 (s, 1H), 8.08 (s, 1H), 4.99 (s, 1H), 3.88–3.95 (m, 2H), 3.13 (s, 3H), 2.99 (s, 3H), 1.07 (t, 3H, J=7.03 Hz); MS m/z 210.86 (M+), 232.87 (M++Na)
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:18][CH3:19])=[C:6]([C:10]2[CH:15]=[CH:14][C:13](C=O)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:20][CH2:21][CH2:22][NH2:23].BrN1C(=O)CC[C:26]1=O>ClCCl>[CH3:19][O:18][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][C:6]=1[C:10]1[CH:11]=[CH:12][C:13]([N:20]2[CH2:21][CH2:22][N:23]=[CH:26]2)=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(-c2ccc(C=O)cc2)cccc1[N+](=O)[O-]
Reactant: NCCN
Solvent: ClCCl
Product: COc1c(-c2ccc(N3C=NCC3)cc2)cccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a solution of 3′-nitro-2′-methoxy-biphenyl-4-carbaldehyde 32a (4.0 g, 15.5 mmol) in 40 mL of dichloromethane under stirring, upon cooling by an ice-water bath, was added 1,2-diaminoethane (981 mg, 16.3 mmol). After the mixture was stirred for another 0.5 hours, 1-bromo-pyrrolidine-2,5-dione (2.91 g, 16.33 mmol) was added. Upon completion of the addition, the ice-water bath was removed. The reaction mixture was stirred overnight at room temperature. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound 2-[(2′-methoxy-3′-nitro-biphenyl-4-yl]-4,5-dihydro-1H-imidazole 32b (4.0 g, 86.9%) as yellow solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:36][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: Cc1cccnc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO[Si](C)(C)C(C)(C)C)C4)CC2)cc1
Agent: Cl
Solvent: CO
Product: Cc1cccnc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO)C4)CC2)cc1
Yield: 84.2 %

Procedure:
A solution of the compound (430 mg, 0.83 mmol) obtained in Example 24-1) and 4 M hydrochloric acid (1,4-dioxane solution, 2 mL) in methanol (2 mL) was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (284 mg, 85%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:16]=[C:17]([C:32]([NH2:34])=[O:33])[C:18]3[NH:19][C:20]4[C:25]([C:26]=3[CH:27]=2)=[CH:24][CH:23]=[C:22]([C:28](O)([CH3:30])[CH3:29])[CH:21]=4)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.Cl.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:16]=[C:17]([C:32]([NH2:34])=[O:33])[C:18]3[NH:19][C:20]4[C:25]([C:26]=3[CH:27]=2)=[CH:24][CH:23]=[C:22]([C:28]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)([CH3:30])[CH3:29])[CH:21]=4)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccc(CN4CCOCC4)c(Cl)c3)cc12
Reactant: C1COCCN1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(c1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccc(CN4CCOCC4)c(Cl)c3)cc12)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
3-(3-Chloro-4-(morpholinomethyl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (40.3 mg, 0.080 mmol, Example 399) was suspended in HCl (1 M solution in diethyl ether) (5 ml, 5.00 mmol) and sonicated briefly. (not completely dissolved. DCM was added (5 ml) in an unsuccessful attempt to dissolve more). The suspension was stirred at room temperature for 1 hour, then cooled to 0° C. Morpholine (5 ml, 57 4 mmol) was added, the ice bath removed and the mixture stirred at room temperature for 3 days. The reaction mixture was poured into a separating funnel that is loaded with EtOAc and sat. aq. NaHCO3 solution. Layers were separated, the aqueous extracted once more with EtOAc and the organic layer washed with brine, then dried over MgSO4, filtered and evaporated. The crude was purified by prep HPLC. Product containing fractions were filtered through a Waters MCX cartridge (1 g adsorbent), washed with MeOH and the product eluted with a 2M solution of NH3 in MeOH. Evaporation to dryness under a stream of nitrogen gave 10.8 mg white 3-(3-chloro-4-(morpholinomethyl)phenyl)-7-(2-morpholinopropan-2-yl)-9H-carbazole-1-carboxamide. MS (ESI) m/e−=545, m/e+=547 consistent with [M−H]− and [M+H]+. HPLC retention time 5.60 min. (Sunfire C18 3.5 μm, 3.0×150 mm column, 15 min gradient, 10-100% B, 0.5 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA). 1H NMR (CD3OD) δ ppm 8.50 (d, 1H, J=1.7), 8.17 (d, 1H, J=1.5), 8.12 (d, 1H, J=8.3), 7.87 (d, 1H, J=1.7), 7.80 (d, 1H, J=0.7), 7.74 (dd, 1H, J=8.0, 1.8), 7.61 (d, 1H, J=8.1), 7.52 (dd, 1H, J=8.2, 1.6), 3.75-3.68 (m, 10H), 2.61-2.54 (m, 8H), 1.49 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](Cl)=[N:11][CH:10]=1.[CH2:34]([CH2:36][NH2:37])[OH:35]>>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([NH:37][CH2:36][CH2:34][OH:35])=[N:11][CH:10]=1
Reactant: NCCO
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1ccccc1-c1cc(NCCO)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 48 h
Yield: 73.9 %

Procedure:
A mixture of 0.837 g (1.72 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-N-methyl-4-o-tolyl-nicotinamide and 5.0 ml (83 mmol) ethanolamine was stirred at 100° C. for 48 h. After cooling to room temperature excess ethanolamine was removed under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with two portions of ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution and water, dried with sodium sulfate and concentrated to give 0.8 g of crude product. Flash chromatography afforded 0.650 g (73.9%) of the title compound as a white solid. MS m/e (%): 512 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:10]=2)[C:5]([Cl:21])=[CH:4][N:3]=1.[CH2:22]([N:24]1[CH2:30][CH2:29][C:28]2[CH:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:27]=2[CH2:26][CH2:25]1)[CH3:23].Cl.C(=O)([O-])[O-]>COCCO.O1CCOCC1>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:10]=2)=[N:7][C:2]([NH:35][C:32]2[CH:33]=[CH:34][C:27]3[CH2:26][CH2:25][N:24]([CH2:22][CH3:23])[CH2:30][CH2:29][C:28]=3[CH:31]=2)=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(Nc2cccc(N3CCOCC3)c2)n1
Reactant: CCN1CCc2ccc(N)cc2CC1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCO
Solvent: C1COCCO1
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(Nc4cccc(N5CCOCC5)c4)n3)cc2CC1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(3-morpholin-4-yl-phenyl)-amine (96 mg, 0.29 mmol) was added into a vial, followed by a solution of 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (52 mg, 0.27 mmol) in 2-Methoxyethanol (2.7 mL). 4 M of Hydrogen chloride in 1,4-Dioxane (0.10 mL) was added and the reaction was heated at 120° C. After 6 h, the reaction was cooled and Macroporous carbonate resin (3.16 mmol/g loading; 400 mg, 1.25 mmol) was added and the reaction was stirred overnight, then was concentrated in vacuo onto Celite, and chromatographed (24 g alumina column, EtOAC-5% MeOH:EtOAC-5% MeOH:DCM). 5-Chloro-N*2*-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo-[d]azepin-7-yl)-N*4*-(3-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine was isolated as a yellow foam (64 mg, 49%). LCMS (m/e) 479 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.01 (s, 1H), 7.47 (m, 2H), 7.37 (d, 1H, J=2.0 Hz), 7.14 (dd, 1H, J=2.3, 8.1 Hz), 6.96 (d, 1H, J=7.9 Hz), 6.92 (m, 3H), 6.82 (s, 1H), 3.89 (t, 4H, J=4.8 Hz), 3.16 (t, 4H, J=4.8 Hz), 2.85 (m, 4H), 2.63 (m, 4H), 2.57 (q, 2H, J=7 Hz), 1.10 (t, 1H, J=7 Hz).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:9][OH:10])(C)(C)C.[Cl:19][CH:20](O)[CH3:21]>>[CH2:15]([O:14][C:12](=[O:13])[NH:11][CH:8]1[CH2:7][C:6](=[O:5])[O:18][CH:9]1[O:10][CH2:21][CH2:20][Cl:19])[CH:16]=[CH2:17]
Reactant: CC(O)Cl
Reactant: C=CCOC(=O)NC(CO)CC(=O)OC(C)(C)C
Product: C=CCOC(=O)NC1CC(=O)OC1OCCCl
Yield: 34.9 %

Procedure:
Prepared from 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester (5.2 g, 20 mmol) as described for 40 using chloroethanol (4.05 mL, 60 mmol) to afford 1.84 g (35% yield) of the title compound as a mixture of epimers. For the anti-diastereomer: 1H-NMR (500 MHz, CDCl3) δ 2.42 (dd, J=18.1 Hz, 1H), 3.00 (dd, J=18.1, 7.8 Hz, 1H), 3.63 (m, 2H), 3.85 (m, 1H), 4.02 (m, 1H), 4.23 (m, 1H), 4.57 (br s, 2H), 5.17 (br s, 1H), 5.22 (d, H=11.5 Hz, 1H), 5.29 (d, J=16.8 Hz, 1H), 5.44 (s, 1H), 5.89 (m, 1H) ppm; LC-MS (ES+) m/e=264 (M+H). For the syn-diastereomer: 1H-NMR (500 MHz, CDCl3) δ 2.47 (dd, J=17.3, 10.7 Hz, 1H), 2.83 (dd, J=17.3, 8.4 Hz, 1H), 3.65 (m, 2H), 3.83 (m, 1H), 4.11 (m, 1H), 4.57 (m, 3H), 5.22 (d, H=10.4 Hz, 1H), 5.30 (d, J=17.2 Hz, 1H), 5.33, (m, 1H, 5.47 (d, J=5.2 Hz, 1H), 5.89 (ddt, J=17.1, 11.0, 5.4 Hz, 1H) ppm; LC-MS (ES+) m/e=264 (M+H).