Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:24]([OH:26])[CH3:25])=[N:14][N:15]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:29]I.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:24]([O:26][CH3:29])[CH3:25])=[N:14][N:15]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(O)c1nn(C2CCCCO2)c2cc(OCc3ccccc3)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)c1nn(C2CCCCO2)c2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1-(6-(Benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-indazol-3-yl) ethanol (10 mg) which can be prepared according to the method described in Reference example 24, etc. was dissolved in dehydrated DMF (0.12 mL; manufactured by Kanto Chemical Co., Inc.), added with sodium hydride-comprising 400 oil (2.0 mg; manufactured by Kanto Chemical Co., Inc.), followed by stirring at room temperature for 5 minutes. To the reaction solution, methyl iodide (4.87 μL; manufactured by Tokyo Chemical Industry, Co., Ltd.) was added and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, which was then extracted twice with ethyl acetate. The organic layer was washed twice with water and once with brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (“COLUMN-F”; n-hexane:ethyl acetate=5:1) to obtain the title compound (10.2 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([OH:12])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:46][C:47]1[S:48][CH:49]=[C:50]([C:52]2[CH:63]=[CH:62][C:55]([C:56]([NH:58][CH:59]3[CH2:61][CH2:60]3)=[O:57])=[CH:54][CH:53]=2)[N:51]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10](=[O:12])[NH:46][C:47]1[S:48][CH:49]=[C:50]([C:52]2[CH:53]=[CH:54][C:55]([C:56](=[O:57])[NH:58][CH:59]3[CH2:61][CH2:60]3)=[CH:62][CH:63]=2)[N:51]=1)=[O:4]
Reactant: Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCC[C@H]1C(=O)Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Reaction time: 0.25 h

Procedure:
Rac-trans-cyclopentane-1,2-dicarboxylic acid monomethyl ester (86 mg) was dissolved in DMF (5 mL) and treated with HATU (1.1 eq. 214 mg) and DIEA (3 eq, 267 μL) and stirred for 15 minutes. Then 4-(2-amino-thiazol-4-yl)-N-cyclopropyl-benzamide (1 eq, 129.5 mg) was added and the mixture stirred at ambient temperature overnight. The reaction was cooled, filtered and the solvents removed. The resulting mixture was redissolved in 5 ml of 90% DMF, 10% water with 0.1% TFA and purified by reverse phase HPLC to give the product. Yield 14 mg. MS: 414.5 (M+H+); H1-NMR (DMSO-d6): δ(ppm) 12.4 (s, 1H), 8.4 (m, 2H), 7.9-7.7 (m, 5H), 3.6 (s, 3H), 3.2 (m, 2H), 2.8 (m, 1H), 2.0 (m, 2H), 1.7 (m, 4H) 0.7-0.6 (m, 4H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:12][C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])=[N:10]1.[OH:36][C:37]([CH3:42])([CH3:41])[C:38](O)=[O:39].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:38](=[O:39])[C:37]([OH:36])([CH3:42])[CH3:41])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:12][C:11]([C:26]([C:28]([F:31])([F:30])[F:29])([C:32]([F:33])([F:35])[F:34])[OH:27])=[N:10]1
Reactant: CC(C)(O)C(=O)O
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(N3CCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(O)C(=O)N1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 28.1 %

Procedure:
To 1-(2-chloro-phenyl)-5-[4-(piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Step 1 of Example 312, were added 2-hydroxyisobutyric acid (7.0 mg, 0.07 mmol), dichloromethane (1.0 mL), HOBT (15.0 mg, 0.11 mmol), EDAC (21.0 mg, 0.11 mmol), and triethylamine (23.0 uL, 0.17 mmol). The reaction mixture was stirred at room temperature for 12 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to give 10.0 mg of the titled compound as a pale yellow liquid.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:45]=[CH:44][C:13]([C:14]([NH:16][NH:17][C:18]([C:20]2[CH:34]=[CH:33][C:23]([O:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])=[C:22]([O:35][CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[CH:21]=2)=[O:19])=[O:15])=[CH:12][CH:11]=1)=O)(C)(C)C.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>O>[F:49][C:48]([F:51])([F:50])[C:46]([OH:52])=[O:47].[NH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:16][NH:17][C:18]([C:20]2[CH:34]=[CH:33][C:23]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:22]([O:35][CH2:36][C:37]([OH:39])=[O:38])[CH:21]=2)=[O:19])=[O:15])=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(C(=O)NNC(=O)c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1OCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NCc1ccc(C(=O)NNC(=O)c2ccc(OCC(=O)O)c(OCC(=O)O)c2)cc1
Reaction time: 2 h

Procedure:
A solution of t-butyl 4-[3-(4-t-butoxycarbonylaminomethylbenzoyl)carbazoyl]-2-(t-butoxycarbonylmethoxy)phenoxyacetate (100 mg) in a mixture of TFA (9 ml) and water (1 ml) was stored at ambient temperature for 2 hours. The reaction mixture was evaporated to near dryness and excess dry ether was added. The solvents were again removed in vacuo. The solid product was triturated with dry ether, collected and dissolved in 50% aqueous acetic acid (10 ml) with gentle warming. The solution was diluted with water (10 ml) and washed with ether (2×20 ml). The aqueous solution was filtered, diluted with water (20 ml) and lyophilised overnight to give the title compound (69 mg) as a white fluffy solid; NMR Spectrum (DHSO-d6) 4.08 (2H, s), 4.60 (2H, s), 4.62 (2H, s), 6.95 (1H, m), 7.4-7.6 (4H, m), 7.92 (2H, m); Mass Spectrum m/Z 418 (H +H)+ ;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[NH2:13])=[CH:5][CH:4]=1.[O:14]=[C:15](Cl)OC(Cl)(Cl)Cl.C(N(CC)CC)C>O1CCOCC1>[N:13]([C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][CH:9]=1)=[C:15]=[O:14]
Reactant: COc1ccc2cccc(N)c2c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc2cccc(N=C=O)c2c1

Procedure:
To a solution of the title compound of Step B (5.0 g) in p-dioxane (115 mL) at room temperature was added via syringe diphosgene (4.2 mL) followed by the addition of triethylamine (4.8 mL). The mixture was heated at reflux overnight while stirring. The reaction was monitored by IR (2267 cm-1). The reaction mixture was filtered and the residue was washed with diethyl ether. The filtrate was concentrated under reduced pressure to give 5.8 g of the title compound of Step C as a beige solid which was used without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].[C:13]([N:17]1[CH2:21][CH2:20][O:19][P:18]1Cl)([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[C:13]([N:17]1[CH2:21][CH2:20][O:19][P:18]1[O:12][C:5]1[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=1[CH3:3])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: CC(C)(C)N1CCOP1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(OP2OCCN2C(C)(C)C)c(C)c1
Yield: 75.6 %

Procedure:
The procedure of Example 1 is repeated using 4.4 g (0.11 mol) of sodium hydride with 45 ml of THF, 13.62 g (0.10 mol) of 2,4,6-trimethylphenol in 150 ml of THF and 18.16 g (0.10 mol) of 3-tert-butyl-2-chloro-1,3,2-oxazaphospholidine in 150 ml of THF to give a (75.6%) of colorless liquid: bp. 99°-103° C. (0.01 mm Hg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:13][NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:30]=[C:31]=[O:32])[CH:26]=[CH:27][C:28]=1[Cl:29].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:22][C:23]1[CH:24]=[C:25]([NH:30][C:31](=[O:32])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:13][NH:14]4)=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1n[nH]c2cc(-c3ccc(N)cc3)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1n[nH]c2cc(-c3ccc(NC(=O)Nc4ccc(Cl)c(Cl)c4)cc3)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The mixture of ethyl 6-(4-aminophenyl)-1H-indazole-3-carboxylate (40 mg) and 3,4-dichlorophenylisocyanate in tetrahydrofuran (3 Ml; THF) was stirred at room temperature for 24 h. Ethyl acetate and saturated sodium bicarbonate solution were wadded. The aqueous layer was extracted with ethyl acetate and the combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated by THF/hexane to give ethyl 6-(4-(3-(3,4-dichlorophenyl)ureido)phenyl)-1H-indazole-3-carboxylate (17.4 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)Cl>[CH3:19][C:18]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:20]
Reactant: CC(=O)Cl
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
A suspension of 13.8 g of 3-nitroaniline and 20 mL of triethylamine in 200 mL methylene chloride was cooled to 0° C. under a nitrogen atmosphere atmosphere and treated with 10.2 g of acetyl chloride, added in a dropwise manner. The reaction mixture was allowed by warm to room temperature overnight. Removal of the volatiles in vacuo gave a crude yellow solid which was washed with 5% aqueous hydrochloric acid, water and was then dried. The yield of 3-nitroacetanilide was 17.4 g as a light yellow solid, m.p. 147°-149° C.; NMR (CDCl3 /DMSO-d6): δ 2.1 (3H, br s), 7.5 (1H, t, J=9 Hz), 8.0 (2H, br t), 8.6 (1H, br s) 10.1 (1H, br s); IR(KBr): 1675, 1550, 1525, 1350 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](Cl)=[O:37])=[CH:31][CH:30]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]2)[C:36](=[O:37])[CH2:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCC(Nc2ccc(Cl)cc2)CC1
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC(N(C(=O)Cc2ccc(OC)cc2)c2ccc(Cl)cc2)CC1

Procedure:
To a stirred solution of 15 parts of ethyl 4-[(4-chlorophenyl)amino]-1-piperidinecarboxylate, 5.4 parts of N,N-diethylethanamine and 160 parts of benzene is added dropwise 11.07 parts of 4-methoxybenzeneacetyl chloride at a temperature between 32° to 40° C. After the addition is complete, the whole is stirred and refluxed for 3 hours. The reaction mixture is cooled and filtered. The filtrate is washed successively with water, sodium hydrogen carbonate solution and water, dried, filtered and evaporated in vacuo. The oily residue is crystallized from a mixture of 56 parts of 1,1'-oxybisethane and 40 parts of hexane. The crude solid product is filtered off and recrystallized from a mixture of benzene and 1,1'-oxybisethane, yielding 3 parts of ethyl 4-{N-(4-chlorophenyl)-N-[(4-methoxyphenyl)acetyl]amino}-1-piperidinecarboxylate; mp. 137° C.
Reaction SMILES: [C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[CH2:25]Cl)[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1>[C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]2([CH2:14][C:15]3[C:16](=[CH:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=3)[CH2:25]2)[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cc2cc(C(F)(F)F)ccc2CCl)c2cccnc21
Solvent: Cc1ccccc1
Product: CC(C)(C)N1C(=O)C2(Cc3ccc(C(F)(F)F)cc3C2)c2cccnc21
Yield: 92.5 %

Procedure:
A solution of 16 (50 mg, 0.126 mmol) in toluene (2 ml) was cooled to −1° C., degassed with vacuum and flushed N2. To this solution was charged a precooled (−2 to 0° C.) aqueous NaOH (1N, 1 mL) followed by charged a catalyst 18. The resulted reaction was aged at −1 to 1° C. for several hours until complete conversion. The organic layer was purified with silica gel column chromatography (0 to 10% AcOEt/hexane) to give the desired compound 17 as oil (42 mg, 92% IY, 85% ee, R or S undetermined).
Reaction SMILES: O=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[NH:20]1[CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[N:20]1([CH:2]2[CH2:19][CH2:18][C:5]3([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[CH2:4][CH2:3]2)[CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Reactant: C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC2(CCC(N3CCC3)CC2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
tert-Butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (stage (iv) Amine-F43) (1 g, 3.74 mmol) and azetidine (0.25 ml, 3.74 mmol) were placed in 1,2-dichloroethane (15 ml), and sodium triacetoxyborohydride (1.1 g, 5.23 mmol) was added. The reaction mixture was stirred for 3 d at room temperature, and then saturated sodium hydrogen carbonate solution was added. After phase separation, the aqueous phase was extracted with dichloromethane (2×). The combined organic phases were washed with saturated sodium chloride solution (1×), dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (silica gel, ethyl acetate/methanol/ammonia (25% aq.), 100:10:1). Yield: 1 g (89%)
Reaction SMILES: C[C:2]1[N:6]2[C:7]([NH2:15])=[C:8]([Cl:14])[CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]2=[N:4][C:3]=1[CH3:16].[CH3:17][O:18][C:19]([CH3:30])([CH3:29])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][NH2:28])[CH2:23][CH2:22]1>>[NH2:15][C:7]1[N:6]2[CH:2]=[C:3]([CH3:16])[N:4]=[C:5]2[C:10]([C:11]([NH:28][CH2:27][CH:24]2[CH2:23][CH2:22][N:21]([CH2:20][C:19]([O:18][CH3:17])([CH3:29])[CH3:30])[CH2:26][CH2:25]2)=[O:13])=[CH:9][C:8]=1[Cl:14]
Reactant: COC(C)(C)CN1CCC(CN)CC1
Reactant: Cc1nc2c(C(=O)O)cc(Cl)c(N)n2c1C
Product: COC(C)(C)CN1CCC(CNC(=O)c2cc(Cl)c(N)n3cc(C)nc23)CC1

Procedure:
The title compound was prepared according to the procedure described in the step 6 in EXAMPLE 1 from 5-amino-6-chloro-2-methylimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 1, Step 5) and [1-(2-methoxy-2-methylpropyl)piperidin-4-yl]methylamine (EXAMPLE 4, Step 6).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Br[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12].C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])[CH:4]=[CH:5][N:6]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: Cc1nccn1-c1cccc(C#N)c1
Yield: 23.5 %

Procedure:
To a stirred solution of 2-methylimidazole (25 g, 0.3 mol) and 3-bromobenzo-nitrile (55 g, 0.3 mol) in pyridine (60 mL) was added K2CO3 (42 g), CuO (1.5 g), Cu powder (1.5 g) and CuBr (1.5 g) under a nitrogen atmosphere. The resulting mixture was heated at reflux temperature for 64 hr. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane-methanol (10:1) to afford 12.9 g (23%) of 3-(2-methylimidazol-1-yl)benzonitrile as white solids.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH3:6][CH:7]1[C:13]2[NH:14][C:15](=O)[CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][N:9]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:8]1>CN(C=O)C>[Br:3][C:15]1[CH:16]=[CH:17][C:12]2[CH2:11][CH2:10][N:9]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:8][CH:7]([CH3:6])[C:13]=2[N:14]=1
Reactant: O=P(Br)(Br)Br
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2ccc(=O)[nH]c21
Solvent: CN(C)C=O
Product: CC1CN(C(=O)C(F)(F)F)CCc2ccc(Br)nc21
Temperature: 90 °C
Yield: 55.6 %

Procedure:
TFA (9.20 mmol, 0.709 ml) was slowly added to a stirred solution of tert-butyl 4-hydroxy-9-methyl-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (0.541 g, 1.84 mmol) in DCM (20 ml) at room temperature. The reaction solution was stirred until all starting materials are consumed. The solvent was removed under reduced pressure and the resulting residue was dissolved in DCM (20 ml). Addition of Et3N (18.4 mmol, 2.56 ml) and TFAA (3.86 mmol, 0.511 ml) was followed by stirring for 8 h at room temperature. The reaction mixture was parted between sat. aq. NaHCO3 and DCM. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified to provide 277 mg (52%, two steps) of 4-hydroxy-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one. MS (ESI) m/z 291 [M+1]+. POBr3 (0.533 mol, 153 mg) was added to a stirred solution of 4-hydroxy-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one (77 mg, 266 μmol) in DMF (1 ml). The mixture was heated at 90° C. for 2 h, quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography to furnish 47 mg (50%) of 4-bromo-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one. MS (ESI) m/z 353/355. A mixture of 4-bromo-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one (47 mg, 134 μmol), EtOH (2 ml) and 10% Pd/C was stirred for 5 minutes under H2 atmosphere (1 atm). The reaction was filtered through Celite and 35 mg (99%) of 9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one was obtained. MS (ESI) m/z 275. POBr3 (256 μmol, 73.5 mg) was added to a stirred solution of 9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one (35 mg, 128 μmol) in DMF (1 ml). The mixture was heated at 90° C. for 5 h, quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography to furnish 24 mg (56%) of 2-bromo-9-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. MS (ESI) m/z 337/339. Deprotection was carried out at 60° C. for 10 minutes using MeOH (1 ml), H2O (200 μl) and K2CO3 (30 mg) to render 15 mg (87%) of 2-bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (DMSO-d6) δ 7.42 (d, 1H), 7.35 (d, 1H), 4.25 (m, 2H), 3.86 (m, 2H), 3.18 (m, 2H), 2.84 (dd, 1H), 1.21 (d, 3H) ppm.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].CN(C)C.Cl[C:15]([O:17][CH2:18][C:19]#[CH:20])=[O:16].C(Cl)Cl.O>C(Cl)Cl>[C:1]([O:6][CH2:7][CH2:8][O:9][C:15]([O:17][CH2:18][C:19]#[CH:20])=[O:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C#CCOC(=O)Cl
Reactant: C=C(C)C(=O)OCCO
Agent: CN(C)C
Solvent: O
Solvent: ClCCl
Product: C#CCOC(=O)OCCOC(=O)C(=C)C
Yield: 73.6 %

Procedure:
A flask equipped with a stirrer, thermometer, nitrogen gas tube and reflux condenser was charged with 13.0 g of 2-hydroxyethyl methacrylate and 11.5 g of trimethylamine in 50.0 g of methylene chloride. To the flask was added 13.0 g of propargyl chloroformate dropwise over one hour. The mixture was allowed to react for 6 hours at 30° C. After the reaction, the mixture was treated with methylene chloride-water mixture. The organic phase was separated and dried over magnesium sulfate. After filtering, the filtrate was evaporated in a rotary evaporator. The resulting residue was applied on a 200 mesh silica gel column and developed with ethyl acetate-hexane mixture. The title compound was obtained as colorless liquid. Yield was 73.6% of theory.
Reaction SMILES: C[O:2][C:3]([CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:4].Cl>[OH-].[Na+].C1COCC1>[N:6]1([CH2:5][C:3]([OH:4])=[O:2])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: COC(=O)CN1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CN1CCOCC1
Yield: 90.3 %

Procedure:
A solution of methyl N-morpholinoacetate (0.85 g, 5.3 mmol) in 1:1 5N NaOH/THF (10 ml) was stirred at 50° C. for 1 h then neutralized to pH 3 with 6N HCl and concentrated. The yellowish solid was diluted with 1:1 MeOH/CH2Cl2 (25 ml), filtered to remove inorganic salts, and concentrated. The dilution, filtration and concentration were repeated to give morpholin-4-yl-acetic acid (695 mg, 90%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[NH:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([O:19][CH2:18][CH2:17][CH2:16][C@:13]1([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:14][CH2:15][N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH3:9])[C:11](=[O:27])[NH:12]1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)NC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCOS(C)(=O)=O)(c2ccc(F)cc2)NC1=O
Temperature: 25 °C
Yield: 94.1 %

Procedure:
To a solution of (R)-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-4-(3-hydroxypropyl)tetrahydropyrimidin-2(1H)-one (50 mg, 0.12 mmol) and triethylamine (161 mg, 1.59 mmol) in CH2Cl2 (5 mL) was added methanesulfonyl chloride (91 mg, 0.8 mmol) at 0° C., and the reaction mixture was stirred at rt till the reaction was over. The reaction was quenched with H2O, and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give crude 3-((R)-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-2-oxohexahydropyrimidin-4-yl)propyl methanesulfonate (58 mg, 95%), which was used for the next step without further purification.