Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH2:4][C:5]([OH:7])=[O:6].Cl.[CH2:17](O)[CH3:18]>>[CH3:15][N:2]([CH3:1])[CH:3]([C:8]1[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=1)[CH2:4][C:5]([O:7][CH2:17][CH3:18])=[O:6]
Reactant: CN(C)C(CC(=O)O)c1ccc(F)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CC(c1ccc(F)cc1)N(C)C
Temperature: 25 °C

Procedure:
A cold solution of 4.0 g of 3-dimethylamino-3-(4-fluorophenyl)propionic acid in 75 ml of ethanol was saturated with hydrogen chloride gas. The mixture was heated at reflux for approximately 16 hours and cooled to room temperature. The mixture was concentrated under vacuum and the residue was dissolved in water. The resulting mixture was washed with diethyl ether and the aqueous phase was made basic with 5N sodium hydroxide. The aqueous phase was extracted twice with diethyl ether and the ether extracts were combined, and washed with water, and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The organic phase was concentrated under vacuum to provide 2.83 g of ethyl 3-dimethylamino-3-(4-fluorophenyl)propionate as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[NH2:12].[CH3:14][C:15]1[CH:19]=[C:18]([CH2:20][C:21](O)=[O:22])[O:17][N:16]=1.CCOC(C)=O>O=P(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[NH:12][C:21](=[O:22])[CH2:20][C:18]1[O:17][N:16]=[C:15]([CH3:14])[CH:19]=1
Reactant: Cc1cc(CC(=O)O)on1
Reactant: COC(=O)c1cc(C#N)ccc1N
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(C#N)ccc1NC(=O)Cc1cc(C)no1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A solution of 2-amino-5-cyano-benzoic acid methyl ester (1.50 g, 8.51 mmol) and (3-methyl-isoxazol-5-yl)-acetic acid (1.32 g, 9.36 mmol) in 40 ml of POCl3 was heated at 80° C. for 2 hr and then cooled to RT. Treated with 50 mL of EtOAc, the mixture was washed with H2O (3×40 ml), sat. NaHCO3 (40 ml), brine (40 ml) and dried (Na2SO4). Removal of the solvent under reduced pressure gave 2.31 g (91%) of product as a light yellow solid: 1H-NMR (CDCl3; 400 MHz) δ 11.49 (s, 1H), 8.85 (d, 1H, J=8.8 Hz), 8.35 (d, 1H, J=2.0 Hz), 7.79 (dd, 1H, J=8.8, 2.0 Hz), 6.20 (s, 1H), 3.97 (s, 3H), 3.95 (s, 2H), 2.33 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C15H13N3O4, 300.1 (M+H), found 299.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](O)[CH:10]=1)[C:5]([OH:7])=[O:6].[C:12]([O-])([O-])=O.[Cs+].[Cs+].CI.O.CN([CH:24]=[O:25])C>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:25][CH3:24])[CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(O)cc(Br)c1
Agent: [Cs+]
Solvent: O
Solvent: CI
Product: COC(=O)c1cc(Br)cc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A mixture of 3-bromo-5-hydroxy-benzoic acid (3 g, 13.8 mmol, 1.0 eq) and Cs2CO3 (13.5 g, 41.5 mmol, 3.0 eq) in DMF (60 mL) was stirred at room temperature for 1 h. Methyl iodide (4.9 g, 34.6 mmol, 2.5 eq) was added and the reaction was stirred at room temperature overnight. The resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a colourless oil (3 g, 88%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[CH2:13][C@@H:14]1[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.O>[CH3:19][C:16]1([CH3:20])[O:15][C@H:14]([CH2:13][O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:18][O:17]1
Reactant: CC1(C)OC[C@@H](CCl)O1
Reactant: COC(=O)c1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(OC[C@@H]2COC(C)(C)O2)c1
Temperature: 160 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
A mixture of methyl 3-hydroxybenzoate (10.0 g, 65.8 mmol), (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (13.0 g, 98.7 mmol) and K2CO3 (18.0 g, 132 mmol) in DMF (100 ml) was stirred for 18 h at 160° C. The mixture was diluted with water (150 mL) and adjusted to pH=6 by the addition of 3N HCl. The mixture was extracted with ethyl acetate (200 ml×3) and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography (10% Ethyl acetate in petroleum ether) to give (R)-methyl 3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzoate as a brown oil, (8.5 g, 49% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8][CH2:7]1)=[O:5])C.CCN(C(C)C)C(C)C.CS([C:25]1[N:30]=[C:29]([N:31]2[C:39]3[C:34](=[C:35]([O:40][CH2:41][CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32]2)[CH:28]=[CH:27][N:26]=1)=O.O>CC(N(C)C)=O>[CH3:1][O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:25]2[N:30]=[C:29]([N:31]3[C:39]4[C:34](=[C:35]([O:40][CH2:41][CH2:42][CH2:43][S:44]([CH3:47])(=[O:45])=[O:46])[CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32]3)[CH:28]=[CH:27][N:26]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: CS(=O)c1nccc(-n2ccc3c(OCCCS(C)(=O)=O)cccc32)n1
Reactant: CCOC(=O)C1CCC(N)CC1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCC(Nc2nccc(-n3ccc4c(OCCCS(C)(=O)=O)cccc43)n2)CC1
Temperature: 120 °C
Yield: 90 %

Procedure:
4-Amino-cyclohexanecarboxylic acid ethyl ester (550 g) and 815 mL DIPEA were added to 1-(2-methanesulfinyl-pyrimidin-4-yl)-4-(3-methanesulfonyl-propoxy)-1H-indole (746.7 g) in 2.5 L DMA, and the mixture allowed to heat to 120° C. for 4 h and then allowed to cool to room temperature. Water (3 L) was added dropwise and the resulting precipitate was collected by filtration, washed with H2O and MeOH, and dried in vacuo at 48° C. overnight to yield 4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid methyl ester (90%).
Reaction SMILES: [CH:1]([N:4]1[CH:9]2[CH2:10][C:11](=O)[CH2:12][CH:5]1[CH2:6][O:7][CH2:8]2)([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:21][OH:22]>C(O)C>[CH:1]([N:4]1[CH:9]2[CH2:10][C:11](=[N:21][OH:22])[CH2:12][CH:5]1[CH2:6][O:7][CH2:8]2)([CH3:3])[CH3:2]
Reactant: CC(C)N1C2COCC1CC(=O)C2
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)N1C2COCC1CC(=NO)C2
Temperature: 23 °C

Procedure:
A mixture of 9-isopropyl-3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one (CAS no: 99189-30-7)(1.25 g, 6.82 mmol) in ethanol (40 mL) and pyridine (0.8 mL, 10.2 mmol) with hydroxylamine hydrochloride (0.5 g, 7.23 mmol) was refluxed for 6 h. Cooled to 23° C., evaporated all volatiles, partitioned the residue between dichloromethane and sodium carbonate solution, reextracted the aqueous layer with tetrahydrofuran/ethyl acetate, all combined organic layers were dried over Na2SO4, filtered and the solvents evaporated to give the title compound as a dark brown solid. (1.0 g, 74%); MS: m/e=199.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#N)[CH:7]=1)[CH3:2].C(O)=[O:16]>[Al].[Ni]>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=[O:16])[CH:7]=1)[CH3:2]
Reactant: O=CO
Reactant: CCOC(=O)Cc1cccc(C#N)c1
Agent: [Ni]
Agent: [Al]
Product: CCOC(=O)Cc1cccc(C=O)c1
Temperature: 100 °C

Procedure:
To a solution of (3-cyano-phenyl)-acetic acid ethyl ester (4.8 g, 25.4 mmol) in 75% aqueous formic acid was added nickel-aluminum alloy (4.6 g). The mixture was heated at reflux (100° C.) for 2.25 h. The reaction mixture was cooled and was filtered through Celite with the aid of boiling EtOH. The filtrate was diluted with H2and the product was extracted into CHCl3 (3×). The organic solution was stirred with saturated NaHCO3 solution until a pH of 8 was attained. The organic solution was dried over MgSO4, filtered, and concentrated. The product was purified by flash chromatography (5:1 hexanes/EtOAc) to afford the title compound (3.33 g). 1H NMR (400 MHz, CDCl3) δ 7.76-7.79 (m, 2H), 7.47-7.57 (m, 2H), 4.15 (q, 2H), 3.69 (s, 2H), 1.25 (t, 3H); MS 193 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH2:13][CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[CH2:18]2.C(N(CC)CC)C.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:13][CH2:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[N:19]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]2=[O:32])[CH2:18]3)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc(Cl)c(Cl)c4)ccc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 93.2 %

Procedure:
3,4-Dichlorophenylisocyanate (0.19 g, 1.0 mmol) was a added to a mixture of 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (0.31 g, 1.0 mmol) in DMF (20 mL), followed by dropwise addition of triethylamine (0.31 mL). After 1 h, water (20 mL) was added. The solid precipitate was filtered and washed with 4% aqueous HCl, and dried in vacuo providing 1-(3,4-dichloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.43 g, 60% yield); mp 238-240° C.; HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 7.87 (99.70%)1H NMR (DMSO-d6) δ 1.98-2.01 (m, 1H), 2.33-2.46 (m, 1H), 2.57-2.62 (m, 1H), 2.86-3.00 (m, 1H), 4.34 (d, 1H, J=17.4), 4.35-4.79 (m, 3H), 5.11 (dd, 1H, J=13.2, J=5.4), 6.93 (t, 1H, J=5.7), 7.27 (dd, 1H, J=8.7, J=2.4), 7.46 (m, 3H), 7.70 (d, 1H, J=7.8), 7.86 (d, 1H, J=2.1), 9.00 (s, 1H), 10.97 (s, 1H). 13C NMR (DMSO-d6) δ 22.5, 31.2, 42.8, 47.1, 51.5, 117.8, 118.9, 121.9, 122.3, 122.9, 123.0, 127.0, 130.3, 130.9, 140.6, 142.4, 144.5, 154.9, 167.9, 171.0, 172.9. Anal. Calcd for C21H18Cl2N4O4+0.9 CH2Cl2: C, 48.92; H, 3.71; N, 10.42. Found: C, 48.87; H, 3.48; N, 10.73.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:21]1[N:26]([CH3:27])[C:25](=[O:28])[C:24]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:23]([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[N:22]=1.BrC1C=C(C2C(=O)N(C)C(Cl)=NC=2C2C=CN=CC=2)C=CC=1>ClCCl>[CH:1]([NH:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:21]1[N:26]([CH3:27])[C:25](=[O:28])[C:24]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:23]([C:36]2[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=2)[N:22]=1)([CH3:3])[CH3:2]
Reactant: Cc1cccc(-c2c(-c3ccncc3)nc(Cl)n(C)c2=O)c1
Reactant: CC(C)NC[C@H]1CCCN1
Agent: Cn1c(Cl)nc(-c2ccncc2)c(-c2cccc(Br)c2)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(-c2c(-c3ccncc3)nc(N3CCCC3CNC(C)C)n(C)c2=O)c1
Reaction time: 0.17 h

Procedure:
To a 100 mL RBF, was added (R)-isopropyl-pyrrolidin-2-ylmethyl-amine (0.13 g, 0.6 mmol), and 50 mL dichloromethane at 0° C. under nitrogen. 0.28 mL diisopropylethylamine (1.6 mmol) was added drop wise, and stirred for 10 min. 2-Chloro-3-methyl-6-pyridin-4-yl-5-m-tolyl-3H-pyrimidin-4-one (0.16 g, 0.5 mmol) was added in one portion, and stirred at 0° C. to rt for 12 h. (This meta-methyl chloro-intermediate was synthesized by a similar procedure as that of 5-(3-Bromo-phenyl)-2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one.) The mixture was diluted with 100 mL dichloromethane, washed with sat. NaHCO3 and brine. After purified by flash chromatography, the title compound was obtained in 0.219 g as pale yellow solid. MS (ES+): 418 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]([N:9]([CH3:22])[C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16]OS(C)(=O)=O)[CH2:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[C:25]([O-:28])(=[S:27])[CH3:26].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([N:9]([CH3:22])[C@H:10]2[CH2:11][CH2:12][C@H:13]([CH2:16][S:27][C:25](=[O:28])[CH3:26])[CH2:14][CH2:15]2)=[O:8])=[CH:23][CH:24]=1
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1
Temperature: 100 °C

Procedure:
To 1.72 g (4.58 mmol) trans-Methanesulfonic acid 4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexylmethyl ester in 17 ml DMF, 0.78 g (6.86 mmol, 1.5 eq) potassium thioacetate were added and the mixture was heated to 100° C. for 10 min. The mixture was concentrated under vacuum and the residue was dissolved in saturated NaHCO3/Et2O (3×). The organic phases were washed with brine, dried over Na2SO4 and evaporated to yield 1.69 g (quantitative) of trans-Thioacetic acid S-{4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexylmethyl}ester, MS: 356 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[CH2:6][C:5]2[CH:7]=[C:8]([C:11]3[C:16](=[O:17])[N:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][CH:20]=4)[C:14]([CH2:33][CH2:34][CH3:35])=[N:13][C:12]=3[CH2:36][CH3:37])[CH:9]=[CH:10][C:4]=2[O:3]1.Cl.[NH2:40]O.[C:42](=[O:45])([O-])[OH:43].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH3:38][C:2]1([CH3:1])[CH2:6][C:5]2[CH:7]=[C:8]([C:11]3[C:16](=[O:17])[N:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:31]5[NH:40][C:42](=[O:45])[O:43][N:32]=5)=[CH:21][CH:20]=4)[C:14]([CH2:33][CH2:34][CH3:35])=[N:13][C:12]=3[CH2:36][CH3:37])[CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: CCCc1nc(CC)c(-c2ccc3c(c2)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(-c2ccc3c(c2)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
4′-{[5-(2,2-Dimethyl-2,3-dihydro-1-benzofuran-5-yl)-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.58 g) was dissolved in dimethyl sulfoxide (5 mL), and hydroxylamine hydrochloride (0.71 g) and sodium hydrogen carbonate (1 g) were added. The mixture was stirred overnight at 90° C. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The residue was dissolved in tetrahydrofuran (5 mL), and N,N′-carbonyldiimidazole (0.25 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added. After stirring for 30 min, the reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.48 g, 74%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:8]1([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)CBr
Reactant: C1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCCCC1
Reaction time: 2 h
Yield: 63.6 %

Procedure:
Ethyl bromoacetate (8.5 g, 50.9 mmol) was added dropwise to a stirred solution of piperidine (4.3 g, 50.5 mmol) and triethylamine (5.5 g, 54.4 mmol) in chloroform (20 ml) at such a rate as to maintain a gentle reflux. After the addition was complete stirring was continued for 2 hours and the reaction mixture washed with water (20 ml×3). The chloroform layer was dried (MgSO4) filtered and the solvent evaporated to leave a yellow oil. This oil was passed through a short column of silica eluting with a CH2Cl2/Pet Ether 40:60 mixture (1:1). Removal of the solvent from the resulting solution gave the required product as a pale yellow oil (Yield 5.5 g, 64%).
Reaction SMILES: N[C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][CH2:7][N:8]3[CH:19]=[CH:18][CH:17]=[C:9]3[C:10](=[CH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:4]=2[CH:3]=1.[CH2:22]=O.[C:24]([BH3-])#[N:25].[Na+]>C(O)(=O)C>[CH3:22][N:25]([CH3:24])[C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][CH2:7][N:8]3[CH:19]=[CH:18][CH:17]=[C:9]3[C:10](=[CH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:4]=2[CH:3]=1
Reactant: [BH3-]C#N
Reactant: CN(C)CCC=C1c2cc(N)ccc2CCn2cccc21
Reactant: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)CCC=C1c2cc(N(C)C)ccc2CCn2cccc21
Reaction time: 0.25 h

Procedure:
To a solution of 9-amino-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine (2.0 g., 10 mmoles) and 4 ml. (50 mmoles) of 37% aqueous formaldehyde in 15 ml. of acetonitrite is added 1 g. (16 mmoles) of sodium cyano borohydride. A vigorous and exothermic reaction takes place and a dark residue separates. The mixture is stirred for 15 minutes and then glacial acetic acid is added dropwise until the solution tests neutral on wet pH paper. Stirring is maintained for an additional 2 hours. The volatiles are removed under vacuum, and the residue is dissolved in chloroform. The solution is washed with base and with water, dried over sodium sulfate, and concentrated to leave a residue that is purified by chromatography on silica gel. Elution with chloroformmethanol yields 9-dimethylamino-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine.
Reaction SMILES: [N:1]1[C:8](Br)=[N:7][C:5](Br)=[N:4][C:2]=1[Br:3].[C:10](=[O:13])(O)[O-].[Na+].[CH3:15][OH:16]>O>[Br:3][C:2]1[N:4]=[C:5]([O:16][CH3:15])[N:7]=[C:8]([O:13][CH3:10])[N:1]=1
Reactant: O=C([O-])O
Reactant: Brc1nc(Br)nc(Br)n1
Reactant: CO
Agent: [Na+]
Solvent: O
Product: COc1nc(Br)nc(OC)n1
Reaction time: 2 h

Procedure:
A mixture of 3.17 g. (0.01 mole) of cyanuric bromide, 1.78 g sodium bicarbonate and 18 ml. methanol was heated under refluxing conditions with stirring for 2 hours. The mixture was cooled and diluted with 50 ml. water. The product was isolated by filtration, washed with water and dried, giving 1.79 g. of white solid, m.p. 118°-120°C.; crystallized from 75 ml. cyclohexane, m.p. 120°-121°C.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=1.C(N(C(C)C)CC)(C)C.CS([Cl:30])(=O)=O>C1COCC1>[Cl:30][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(CO)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.6 %

Procedure:
To a solution of tert-butyl 5-(hydroxymethyl)pyridin-2-ylcarbamate 116 (85.0 g, 379 mmol) and diisopropylethylamine (296 g, 2.27 mol) in THF (850 mL) was added methanesulfonyl chloride (130 g, 1.14 mol) over a period of 30 min at 0° C. The mixture was stirred for 12 h at room temperature then washed with H2O (2×100 mL) and dried over Na2SO4. The mixture was concentrated and the crude residue was purified by flash chromatography (petroleum ether: ethyl acetate=10:1) to give 117 (30 g, 63% yield).
Reaction SMILES: [C:1]([C@@H:4]1[NH:9][CH2:8][CH2:7][N:6]([S:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:12])=[O:11])[CH2:5]1)#[C:2][CH3:3].Cl[C:19]1[N:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=1.C(N(CC)CC)C>O1CCOCC1>[F:29][C:26]([F:27])([F:28])[C:25]([C:22]1[CH:23]=[N:24][C:19]([N:9]2[CH2:8][CH2:7][N:6]([S:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)(=[O:12])=[O:11])[CH2:5][C@@H:4]2[C:1]#[C:2][CH3:3])=[N:20][CH:21]=1)([OH:34])[C:30]([F:33])([F:32])[F:31].[F:29][C:26]([F:27])([F:28])[C:25]([C:22]1[CH:23]=[N:24][C:19]([N:9]2[CH2:8][CH2:7][N:6]([S:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)(=[O:12])=[O:11])[CH2:5][C@H:4]2[C:1]#[C:2][CH3:3])=[N:20][CH:21]=1)([OH:34])[C:30]([F:33])([F:32])[F:31]
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: CC#C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC#C[C@@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Product: CC#C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Temperature: 100 °C

Procedure:
In a 50-mL sealed vial, a mixture of (S)-3-(prop-1-yn-1-yl)-1-(thiophen-2-ylsulfonyl)piperazine (40 mg, 0.148 mmol), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (41.5 mg, 0.148 mmol), and triethylamine (30.9 μl, 0.222 mmol) in dioxane was heated to 100° C. for 16 h. Afterwards, the mixture was concentrated and the crude material was purified via column chromatography (about 40 g silica gel, 0% to 10% MeOH in CH2Cl2) to give the racemate of 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-(1-propyn-1-yl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol (18 mg) and 1,1,1,3,3,3-hexafluoro-2-(2-((2R)-2-(1-propyn-1-yl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol (18 mg).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[OH2:11].[C:12]([O:15][CH2:16][CH3:17])(=[O:14])[CH3:13]>CN(C)C=O>[O:11]=[C:5]1[CH:10]([CH2:2][C:3](=[O:4])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:13][C:12]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O
Reactant: CCOC(C)=O
Reactant: O=C(CBr)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCCC(CC(=O)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
Intermediate 2 (667 mg, 2.81 mmol) was dissolved in dimethylformamide (14 ml), 2-bromo-1-phenylethanone (560 mg, 2.81 mmol) was added and the reaction stirred for 24 h at room temperature. Water (5 ml) was added and the reaction allowed to stir for a further 24 h. The mixture was then diluted with ethyl acetate (100 ml) and washed with water. The aqueous fraction was re-extracted three times with ethyl acetate and the combined organic fractions washed three times with water, then dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography (10-20% ethyl acetate/hexanes) provided the title compound as a pale yellow oil (428 mg, 50%).
Reaction SMILES: [C:1]([C:5]1[C:6]([C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)=[N:7][CH:8]=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2].[H-].[Na+].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.CCOC(C)=O.CO>CN(C=O)C>[N:22]1([C:15]2[CH:16]=[CH:17][C:12]([C:11]([C:6]3[C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:10][CH:9]=[CH:8][N:7]=3)=[O:19])=[CH:13][CH:14]=2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: COC(=O)c1cccnc1C(=O)c1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1cccnc1C(=O)c1ccc(-n2ccnc2)cc1
Temperature: 120 °C

Procedure:
A solution of 3-carbomethoxy-2-(4-fluorobenzoyl)pyridine (2.38 g, 9.18 mmol) in 7 ml of DMF is added dropwise to a mixture of NaH (0.25 g, 10.56 mmol) and imidazole (0.63 g, 9.18 mmol) in 25 mL of DMF. The mixture is heated at 120° C. for 20 hours, then allowed to cool, quenched with H2O and extracted with CH2Cl2 (4×50 mL). The combined organic layers are dried (Na2SO4) and evaporated to produce an oil. Chromatography on silica gel (using EtOAc-MeOH, 9.5:0.5 as the eluent) gives 2-[4-(1H-imidazol-1-yl)benzoyl]3-carbomethoxypyridine. M.P. 171°-173.5° C.