Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:20])[NH:9][CH:10]([C:12]1[CH:13]=[N:14][C:15]([F:19])=[CH:16][C:17]=1[I:18])[CH3:11])([CH3:6])([CH3:5])[CH3:4].[F:21][CH2:22][CH2:23]I>C(Cl)(Cl)Cl.C(O)(C)C>[F:19][C:15]1[N:14]=[CH:13][C:12]([CH:10]([N:9]([CH2:23][CH2:22][F:21])[C:8](=[O:20])[O:7][C:3]([CH3:4])([CH3:5])[CH3:6])[CH3:11])=[C:17]([I:18])[CH:16]=1
Reactant: CC(NC(=O)OC(C)(C)C)c1cnc(F)cc1I
Reactant: FCCI
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CC(c1cnc(F)cc1I)N(CCF)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 41.5 %

Procedure:
Add sodium hydride (58.9 mg, 2.46 mmol) to a solution of [1-(6-fluoro-4-iodo-pyridin-3-yl)-ethyl]-carbamic acid tert-butyl ester (300 mg, 819 μmol) at 0° C. Stir the mixture at 0° C. to RT for 1 h. Add 1-fluoro-2-iodo-ethane (570 mg, 3.28 mmol). Stir the mixture at RT for 4 h and then at 50° C. overnight. Dilute the mixture with chloroform/IPA (3/1, 100 mL) and wash with water/aqueous saturated sodium chloride. Dry the organic phase over sodium sulfate and concentrate in vacuo to give the crude product. Purify the crude product by FCC (20% ethyl acetate in hexane) to give 140 mg of the title compound (41%). MS (ES) m/z 413 [M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[N:8]=[C:7]([Cl:9])[C:6]([S:10][CH3:11])=[C:5](Cl)[N:4]=1.C1C=CC=CC=1.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH2:25])[CH3:21]>C(N(CC)CC)C>[CH3:21][CH2:20][N:22]([CH2:23][CH2:24][NH:25][C:5]1[N:4]=[C:3]([N:2]([CH3:1])[CH3:13])[N:8]=[C:7]([Cl:9])[C:6]=1[S:10][CH3:11])[CH2:26][CH3:27]
Reactant: CCN(CC)CCN
Reactant: CSc1c(Cl)nc(N(C)C)nc1Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCN(CC)CCNc1nc(N(C)C)nc(Cl)c1SC

Procedure:
23.8 parts of 2-dimethylamino-4,6-dichloro-5-methylthio-pyrimidine are placed in 300 parts by volume of benzene and a solution of 12.2 parts of N,N-diethylethylenediamine and 16 parts of triethylamine is added. The mixture is heated under reflux for three hours. After filtering off the triethylamine hydrochloride, the mixture is concentrated, extracted with ether/water, and the organic phase is concentrated and recrystallised from ethyl alcohol. 2-dimethylamino-4-(2'-diethylamine)ethylamino-5-methylthio-6-chloropyrimidine having a melting point of 56°C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:15]=[CH:16][C:17]=3[O:18][CH3:19])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:37]([CH:34]4[CH2:36][CH2:35]4)=[O:38])[S:3][C:4]=3[CH:10]=2)[CH:13]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]
Reactant: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2c1
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2c1
Yield: 44.8 %

Procedure:
Using N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-methoxyphenyl}-3-(1-cyano-1-methylethyl)benzamide (115 mg, 0.25 mmol), cyclopropanecarbonyl chloride (105 mg, 1.00 mmol), N,N-dimethylpyridine-4-amine (122 mg, 1.00 mmol) and pyridine (2 mL), and in the same manner as in Example A18(v), the title compound (59 mg, 45%) was obtained as a pale-yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][C:15](OCC)=[O:16]>CN(C=O)C>[N:1]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:12][CH2:13][CH2:14][C:15]1=[O:16]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CCCBr
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(N2CCCC2=O)cc1
Reaction time: 0.83 h

Procedure:
19.2 g (140 mmol) 4-amino-benzoic acid are refluxed for 20 hours together with 25.8 ml (180 mmol) ethyl 4-bromobutyrate in 100 ml DMF. After evaporation i. vac. the residue is combined with 100 ml of water and 50 ml petroleum ether and vigorously stirred for 50 minutes. The precipitate is filtered off, recrystallised from ethanol and dried at 80° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.[NH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH2:24])=[O:23].C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:2]([NH:18][CH2:19][CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NCCCC(N)=O
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CCCNc1nc(-c2cccc(Cl)c2)nc2c1CCC2
Yield: 47.9 %

Procedure:
A solution of 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.032 g, 0.12 mmol), 4-aminobutanamide (0.061 g, 0.60 mmol), and N,N-diisopropylethylamine (0.031 g, 0.24 mmol) in NMP (3 mL) was heated at 90° C. overnight. After this time, the reaction mixture was cooled, diluted water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford the title compound (0.019 g, 61%) as a white solid. MW=330.81. 1H NMR (DMSO-d6, 500 MHz) δ 8.31-8.26 (m, 2H), 7.51-7.46 (m, 2H), 7.27 (s, 1H), 7.03 (t, J=5.5 Hz, 1H), 6.73 (s, 1H), 3.48 (q, J=6.7 Hz, 2H), 2.81 (t, J=7.6 Hz, 2H), 2.68 (t, J=7.3 Hz, 2H), 2.16 (t, J=7.6 Hz, 2H), 2.03 (quin, J=7.6 Hz, 2H), 1.84 (quin, J=7.3 Hz, 2H); APCI MS m/z 331 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21]([O:27][C:28]3[CH:41]=[CH:40][C:31]4[C:32]([C:36]([NH:38][CH3:39])=[O:37])=[C:33]([CH3:35])[O:34][C:30]=4[CH:29]=3)=[CH:22][CH:23]=[N:24]2)=[CH:19][CH:18]=1>CN(C=O)C>[CH3:39][NH:38][C:36]([C:32]1[C:31]2[CH:40]=[CH:41][C:28]([O:27][C:21]3[C:20]4[C:25](=[CH:26][C:17]([O:16][CH2:2][CH2:3][N:4]5[CH2:9][CH2:8][O:7][CH2:6][CH2:5]5)=[CH:18][CH:19]=4)[N:24]=[CH:23][CH:22]=3)=[CH:29][C:30]=2[O:34][C:33]=1[CH3:35])=[O:37]
Reactant: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(O)ccc34)ccc12
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(OCCN5CCOCC5)ccc34)ccc12
Temperature: 120 °C
Yield: 19.6 %

Procedure:
A solution of 4-(2-chloroethyl)morpholine (10.7 g, 57.4 mmol) and Cs2CO3 (46.3 g, 143.5 mmol) in DMF (100 mL) was stirred for 1 hour at room temperature. To the solution was added a solution of 6-[(7-hydroxyquinolin-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3-carboxamide (10 g, 28.7 mmol). The mixture was heated to 120° C. for 15 hr. The solution was cooled to room temperature and extracted with EtOAc. The concentrated residue was purified by a silica gel column chromatography (using 5 to 10%) MeOH/CH2Cl2) to give 2.6 g of free base N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinolin-4-yloxy]benzofuran-3-carboxamide as a solid. The solid free base was identified as Form 1 as characterized by powder X-ray diffraction as shown in FIG. 11. Note, Form 1 can also be prepared by slurrying any of Forms 3, 5, or 6 in water at room temperature for 24 hours.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[N:10]=[C:9]([C:19]([OH:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[CH:8]=2)=[CH:4][CH:3]=1.[CH3:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31].C([O-])([O-])=O.[K+].[K+]>>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:11]1[C:7]([C:5]2[S:6][C:2]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:38]=3)=[CH:3][CH:4]=2)=[CH:8][C:9]([C:19]([OH:28])([C:24]([F:27])([F:25])[F:26])[C:20]([F:21])([F:23])[F:22])=[N:10]1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: OC(c1cc(-c2ccc(Br)s2)n(-c2ccccc2Cl)n1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(O)(C(F)(F)F)C(F)(F)F)nn3-c3ccccc3Cl)s2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
A mixture of 2-[5-(5-bromothiophen-2-yl)-1-(2-chlorophenyl)-1H-pyrazol-3-yl]-1,1,1,3,3,3-hexafluoro-propan-2-ol (84 mg, 0.17 mmol), 3-methanesulfonyl-phenylboronic acid (42 mg, 0.21 mmol), K2CO3 (70 mg, 0.51 mmol), Cl2Pd(dppf).DCM (21 mg, 15 mol %) and H2O (0.2 mL) in dioxane (2 mL) was sparged with Argon for 5 min and then heated at 80° C. as a sealed flask. After 3 h the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 0:100 to 50:50) to give the title compound (34 mg) as a white solid. 1H-NMR (DCM-d2): δ 8.03 (m, 1H), 7.83 (m, 1H), 7.76 (m, 1H), 7.55-7.62 (m, 4H), 7.49-7.54 (m, 1H), 7.29 (d, 1H), 6.91 (d, 1H), 6.86 (s, 1H), 5.10 (s, 1H), 3.05 (s, 3H); MS(ES): 581 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[OH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: OCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCc2ccccn2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl amine, 2-(hydroxymethyl)pyridine and DBU in dioxane. 349 (M{81Br}+H+, 98), 347 (M{79Br}+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31](=[O:36])[NH:32][C:33]([NH2:35])=[O:34])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[C:13]([OH:15])=[O:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C([O-])([O-])=O.[K+].[K+].S(OCC)(O[CH2:47][CH3:48])(=O)=O.O>CS(C)=O>[CH2:47]([O:14][C:13](=[O:15])[C:12]([C:16]1[CH:17]=[CH:18][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31](=[O:36])[NH:32][C:33]([NH2:35])=[O:34])=[CH:25][CH:24]=2)=[CH:20][CH:21]=1)=[CH:11][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=1)[CH3:48]
Reactant: CCOS(=O)(=O)OCC
Reactant: COc1cc(C=C(C(=O)O)c2ccc(Oc3ccc(CCC(=O)NC(N)=O)cc3)cc2)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(CCC(=O)NC(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 6 (0.40 g, 0.81 mmol) in dry DMSO (3 mL) was added K2CO3 (0.14 g, 0.98 mmol). To this, diethyl sulfate (0.115 g, 0.91 mmol) was added and stirred at room temperature for 30 min. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by column chromatography over silica gel and eluted with hexanes-ethyl acetate (3:1). Yield: 0.39 g, 92.2%.
Reaction SMILES: [N:1]([CH:4]1[CH2:7][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[CH2:5]1)=[N+]=[N-]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:1][CH:4]1[CH2:5][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(N=[N+]=[N-])C2)C1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Product: CC(C)(C)OC(=O)N1CCC2(CC(N)C2)C1
Yield: 58.4 %

Procedure:
The process is performed according to the procedure described in Example 6 (step 6.4). Starting with 1.33 g (5.30 mmol) of tert-butyl 2-azido-6-azaspiro[3.4]octane-6-carboxylate (isomer 2′) and 0.54 g (2.65 mmol) of Lindlar catalyst (PdCaCO3), 0.70 g of product is obtained in the form of an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[CH:17]1[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[NH:19][CH2:18]1.[CH2:25](Br)[CH:26]=[CH2:27]>C(#N)C>[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[CH:17]1[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[N:19]([CH2:27][CH:26]=[CH2:25])[CH2:18]1
Reactant: O=[N+]([O-])c1ccc(C2CCS(=O)(=O)NC2)c(F)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CC(c2ccc([N+](=O)[O-])cc2F)CCS1(=O)=O

Procedure:
Anhydrous potassium carbonate (3.6 g, 26.1 mmol) is added to a solution of of 4-(2-fluoro-4-nitrophenyl)tetrahydro-2H-1,2-thiazine 1,1-dioxide (1.795 g, 6.54 mmol) and allyl bromide (2.0 ml, 23.1 mmol) in dry acetonitrile (25 ml). The mixture is heated to reflux for 5 min then cooled. After filtration and evaporation the residue is chromatographed over silica gel (150 g) eluting with 0-1% methanol-chloroform. The title compound is obtained as flakes (1.70 g, 83%) mp 121°.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][C@@H:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]1[C:22]([O:24][CH3:25])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[NH2:29]O.Cl>CO.CO.O.O>[CH2:1]([C@H:8]1[CH2:13][C@@H:12]([C:14]2[O:21][NH:29][C:16](=[O:17])[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:22]([O:24][CH3:25])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccccc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of cis-methyl 2-benzyl-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.15 g, 6.18 mmol) (from Example 1, Step 1) in MeOH (0.75 mL) was added to a solution of NaOH (0.26 g, 6.55 mmol) in MeOH/H2O (5 mL/0.3 mL) at −30° C. After 10 minutes was added a solution of hydroxylamine hydrochloride (0.86 g, 12.4 mmol) and NaOH (0.49 g, 12.4 mmol) in MeOH (6.1 mL) and H2O (6.1 mL). Stirring was continued at −30° C. for 30 minutes. The reaction mixture was then poured into concentrated HCl (7 mL) held at 80° C. The solution was stirred for 30 minutes. The organic solvent was evaporated and the aqueous phase extracted with ether (×3). The combined organic phases were dried over Na2SO4, and evaporated to yield a solid, 2.2 g. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 20-70% acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer, over 18 minutes with a flow of 19 mL/minutes. The title compound was isolated (1.1 g, 57%). 1H NMR (600 MHz, cdcl3) δ 1.76-2.15 (m, 4H), 2.63 (m, 1H), 2.82 (m, 1H), 2.87-3.03 (m, 1H), 3.03-3.22 (m, 1H), 3.61 (s, 3H), 3.99 (m, 1H), 4.19-4.33 (m, 1H), 5.71 (s, 1H), 7.01-7.37 (m, 5H). MS m/z 317 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[N:13]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[C:5]([CH3:22])[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:3]1=[O:33].[Br:34]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[Br:34][C:10]1[CH:11]=[N:12][N:13]([C:14]2[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[CH:20][CH:21]=2)[C:9]=1[C:6]1[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:33])[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)[C:5]=1[CH3:22]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(-c2c(Br)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a solution of 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 1) (665 mg) in acetic acid (15 ml) was added at room temperature bromine (0.75 ml) dropwise and the resulting mixture was stirred at room temperature for fifteen minutes. To the reaction mixture was added 10% aqueous sodium thiosulfate solution (30 ml) and the solids formed were filtered and then washed with hexane (50 ml) and dried under reduced pressure to afford 4-(4-bromo-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (692.8 mg) as brown solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:31])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:23]3[CH:24]=[C:25]([CH:26]=[CH:27][CH:28]=3)[C:29]#[N:30])[CH2:20][C:19](=[O:31])[NH:18][C:9]=2[CH:10]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(C#N)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-5-dimethylamino-phenyl}-carbamic acid tert.-butyl ester (Example M1) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (85 mg).
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:33])(=[O:32])[NH:26][CH2:27][CH2:28][CH2:29][C:30]#[N:31])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:41][CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CC#N>[C:30]([CH2:29][CH2:28][CH2:27][N:26]([CH2:41][CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[S:25]([N:20]1[CH2:19][CH2:18][N:17]([C:16]2[C:11]3[CH:10]=[CH:9][NH:8][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:24][C:21]21[CH2:23][CH2:22]2)(=[O:32])=[O:33])#[N:31]
Reactant: BrCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(=O)(=O)NCCCC#N)C4(CC4)C3)ncnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#CCCCN(CCCc1ccccc1)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reaction time: 16 h

Procedure:
4-[4-(3-Cyano-propylsulfamoyl)-4,7-diaza-spiro[2.5]oct-7-yl]-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 18) was dissolved in CH3CN (0.4 mL), added Cs2CO3 and (3-bromo-propyl)-benzene. Stirred at for 16 h and then added additional (3-bromo-propyl)-benzene (2 equivalents) before being stirred at rt for 3 days. The crude reaction mixture was filtered through a syringe filter (0.45 μm) and purified by standard preparative HPLC purification. The residual oil was dissolved in THF (1 mL), added TFA (0.5 mL) and then stirred at rt for 2 h. The crude reaction mixture was concentrated in vacuo and redissolved in MeOH (0.5 mL). The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2].Br[C:44]1[S:45][CH:46]=[CH:47][N:48]=1>>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:44]3[S:45][CH:46]=[CH:47][N:48]=3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2]
Reactant: Brc1nccs1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Product: CCOC(=O)Cc1cccc(Oc2ccc(-c3nccs3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-phenyl}-acetic acid ethyl ester and 2-bromothiazole.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][CH2:9][C:10](O)=[O:11])=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:1][CH2:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1
Reactant: O=C(O)CCOc1ccc(CO)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCOc1ccc(CO)cc1

Procedure:
To a solution of 3-(4-hydroxymethylphenoxy)propionic acid (4.00 g, 20.40 mmol) in THF (20 mL) is added a solution of LiAlH4 (10 mL, 1 M in THF). The mixture becomes warm and is diluted with THF (20 mL) before it is refluxed. After 1 and 2 h two further portions of LiAlH4 (2×10 mL, 1 M in THF) are added. The mixture is refluxed overnight, cooled to it and carefully quenched by the addition of water (1.2 g), 15% aq. NaOH (1.2 g) and water (3.2 g). The white precipitate is filtered off, and the filtrate is evaporated and dried to give 3-(4-hydroxymethyl-phenoxy)-propan-1-ol. 1H NMR (D6-DMSO): δ 7.21-7.15 (m, 2H), 6.86-6.81 (m, 21-1), 5.00 (t, J=5.9 Hz, 1H), 4.51 (t, J=5.3 Hz, 1H), 4.39 (d, J=5.3 Hz, 2H), 3.99 (t, J=6.4 Hz, 2H), 3.57-3.50 (m, 2H), 1.83 (p, J 06.4 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Cl:15])=[C:11](Cl)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+]>CO.C(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Cl:15])=[C:11]([O:18][CH3:17])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cnn(Cc2ccccc2)c(=O)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-benzyl-4,5-dichloro-2H-pyridazine-3-one (22.31 g, 87.47 mmol), prepared as described in Example 244A, in dry MeOH (175 mL) at 0° C., was added dropwise a solution of sodium methoxide in methanol (25% weight in MeOH, 25 mL). The mixture was slowly warmed up to room temperature and stirred for 18 h. The reaction mixture was diluted with methylene chloride (200 mL) and filtered. The filtrate was concentrated to afford the title compound, 2-benzyl-4-chloro-5-methoxypyridazin-3(2H)-one (22.2 g) which was >95% pure as judged by HPLC and was used in the next reaction, Example 354B, without further purification.
Reaction SMILES: FC1C=CC([S:8]([Cl:11])(=[O:10])=[O:9])=CC=1OC.[F:14][C:15]1[CH:16]=[C:17](N)[CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22]>>[F:14][C:15]1[CH:16]=[C:17]([S:8]([Cl:11])(=[O:10])=[O:9])[CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22]
Reactant: Nc1ccc(C(F)(F)F)c(F)c1
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Product: O=S(=O)(Cl)c1ccc(C(F)(F)F)c(F)c1

Procedure:
The titled compound is prepared analogously to 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 3-fluoro-4-trifluoromethyl-phenylamine.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@:9]1([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:10](=O)[C@@H:11]([F:23])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[BH4-].[Na+].[OH-].[Na+]>CO>[CH2:31]([NH:38][C@H:10]1[C@@H:11]([F:23])[CH2:12][C@@H:13]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@:9]1([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:15][C@H:14]2[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(c3ccccc3)C(=O)[C@@H](F)C[C@@H]1N2Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@@H](NCc3ccccc3)[C@@H](F)C[C@@H]1N2Cc1ccccc1
Temperature: 50 °C
Yield: 31.7 %

Procedure:
(1R*,3S*,5S*,6R*)-8-Benzyl-3-fluoro-1-phenyl-6-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octan-2-one (Description 36a; 1.68 g, 4.1 mmol), titanium iso-propoxide (1.8 mL, 6.2 mmol) and benzylamine (520 μL, 4.7 mmol) were heated together at 85° C. for two hours, then cooled and diluted with methanol (30 mL). The solution was then heated to 50° C. and sodium borohydride (1.06 g, 28 mmol) was added portionwise over 4 hours. After addition was complete, the solution was heated for a further 16 hours, then cooled and poured into aqueous sodium hydroxide solution (100 mL, 1M). The suspension formed was extracted with ethyl acetate (2×100 mL) and the extracts were dried (MgSO4). Concentration in vacuo gave a gum which was purified by silica chromatography to give the title compound (651 mg, 1.3 mmol).