Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:22])[C:14]([C:15]3[S:19][C:18](Cl)=[N:17][C:16]=3[Cl:21])=[C:10]2[N:9]=[C:8]([CH3:23])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].CC1OCCC1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>O>[CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:22])[C:14]([C:15]3[S:19][C:18]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[N:17][C:16]=3[Cl:21])=[C:10]2[N:9]=[C:8]([CH3:23])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(Cl)nc3Cl)c(C)nn12
Reactant: C1COCCN1
Solvent: CC1CCCO1
Solvent: O
Product: CCC(CC)c1cc(C)nc2c(-c3sc(N4CCOCC4)nc3Cl)c(C)nn12
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
7-(1-ethyl-propyl)-3-(2,4-dichloro-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (15.2 g, 41.16 mmoles) is charged into a 250 mL 3-necked round bottomed flask, followed by addition of 2-MeTHF (61 mL, 4.0 volumes), the yellowish brown slurry is stirred at about 20° C. for 5 min. Then morpholine (19 g, 218.18 mmoles) is added over 2-5 minutes. Contents are heated to reflux and maintained at reflux for 12 hr. The slurry is cooled to 25° C., followed by addition of 2-MeTHF (53 mL, 3.5 volumes) and water (38 mL 2.5 volumes). The reaction mixture is warmed to 40° C., where upon a homogenous solution with two distinct layers formed. The layers are separated, the organic layer is filtered and concentrated to ˜3 volumes at atmospheric pressure. Four volumes 2-propanol (61 mL) are added. The solution is concentrated to ˜3 volumes followed by addition of 4 volumes 2-propanol (61 mL), re-concentrated to ˜3 volumes, followed by addition of another 6 volumes 2-propanol (91 mL), and refluxed for 15 min. The clear solution is gradually cooled to 75° C., seeded with 0.45 g 7-(1-ethyl-propyl)-3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine slurried in 2 mL 2-propanol, rinsed with an additional 2 mL 2-propanol and transferred to a crystallization flask. The slurry is cooled to between 0-5° C., maintained for 1 hr, filtered and the product rinsed with 2-propanol (30 mL, 2 volumes). The solid is dried at 60° C. in a vacuum oven to afford 16.92 g 7-(1-ethyl-propyl)-3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine. Purity of product by HPLC assay is 100.00%. XRPD and DSC data of product is consistant with reference sample. MS (ES)=420 (M+1).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH2:10][CH2:11][N:12]1[C:16]([CH3:17])=[CH:15][N:14]=[CH:13]1.N1C=CN=C1.C(Cl)Cl>O>[Si:1]([O:9][CH2:10][CH2:11][N:12]1[C:16]([CH3:17])=[CH:15][N:14]=[CH:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1cncn1CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: Cc1cncn1CCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
Tert-butyldimethylsilyl chloride (9.05 g) was added to a stirred mixture of 1-(2-hydroxyethyl)-5-methylimidazole (6.4 g), imidazole (7.5 g) and methylene chloride (30 ml) which was cooled to 0° C. The reaction mixture was stirred at ambient temperature for 4 hours. The mixture was poured into water. The organic layer was washed with brine, dried over magnesium sulphate and evaporated to give 1-(2-tert-butyldimethylsilyloxyethyl)-5-methylimidazole (11.7 g); NMR Spectrum: (CDCl3) −0.04 (s, 6H), 0.85 (s, 6H), 2.2 (s, 3H), 3.8 (m, 2H), 3.94 (m, 2H), 6.75 (s, 1H), 7.43 (s, 1H).
Reaction SMILES: [N:1]12[CH2:15][CH2:14][CH:4]([C:5]3[NH:6][C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[C:13]=31)[CH2:3][CH2:2]2.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]=[CH2:24])=[CH:19][N:18]=1>>[CH3:16][C:17]1[N:18]=[CH:19][C:20]([CH2:23][CH2:24][N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]3[N:1]4[CH2:2][CH2:3][CH:4]([C:5]2=3)[CH2:14][CH2:15]4)=[CH:21][CH:22]=1
Reactant: c1ccc2c3c([nH]c2c1)C1CCN3CC1
Reactant: C=Cc1ccc(C)nc1
Product: Cc1ccc(CCn2c3c(c4ccccc42)N2CCC3CC2)cn1

Procedure:
The coupling of 2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole (110 mg, 0.56 mmol; Example 205A) and 2-methyl-5-vinylpyridine (99 mg, 0.83 mmol; prepared as described in International Publication No. WO 2001017968) was performed according to the procedure described in Example 106A to provide the title compound: 1H NMR (500 MHz, methanol-d4) δ ppm 0.91-1.05 (m, 2H), 1.75-1.85 (m, 2H), 2.38 (s, 3H), 2.42-2.51 (m, 2H), 3.09-3.21 (m, 5H), 4.44-4.50 (m, 2H), 7.02-7.12 (m, 3H), 7.27 (dd, J=7.9, 2.1 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.56 (d, J=7.3 Hz, 1H), 7.77 (d, J=2.1 Hz, 1H); MS (ESI) m/z 476 (M+H)+.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=2)[N:23]=[CH:22][N:21]=1>C(Cl)Cl>[C:1]1([C@H:7]([NH:9][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: C[C@@H](N)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](Nc1ncnc2ccc([N+](=O)[O-])cc12)c1ccccc1
Reaction time: 48 h

Procedure:
A mixture of 6.40 ml of (R)-(1-phenylethyl)amine and 8.70 ml of diisopropylethylamine in 30 ml methylene chloride is added dropwise to 9.00 g of 4-chloro-6-nitroquinazoline in 70 ml methylene chloride while cooling with an ice bath. The mixture is allowed to come up to ambient temperature, then it is stirred for about another 48 hours. For working up, the reaction mixture is washed with water, 10% citric acid, and again with water. The organic phase is dried over magnesium sulfate and concentrated by evaporation. The solid evaporation residue is stirred with about 100 ml methanol, suction filtered, and washed with a little methanol. Yield: 8.44 g (67% of theory); Rf value: 0.33 (silica gel, cyclohexane/ethyl acetate=1:1); mass spectrum (ESI−): m/z=293 [M−H]−.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH3:11])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.O>C(O)C>[C:8]([C:7]1[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:3][C:4]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)=[N:5][C:6]=1[O:10][CH3:11])#[N:9]
Reactant: C1CNCCN1
Reactant: COc1nc(N2CCSCC2)nc(Cl)c1C#N
Solvent: O
Solvent: CCO
Product: COc1nc(N2CCSCC2)nc(N2CCNCC2)c1C#N
Temperature: 130 °C

Procedure:
18 gm (0.067 mol) of 4-chloro-5-cyano-6-methoxy-2-thiomorpholino-pyrimidine (m.p. 218°-219°C) were admixed with 60.3 gm (0.7 mol) of piperazine, and the mixture was heated at 130°C for 3 hours. After cooling, water was added, and the aqueous mixture was extracted with chloroform. The chloroform phase was dried, and the chloroform was removed in vacuo. The residue, the free base reaction product, was dissolved in hot ethanol, and the hydrochloride was precipitated by addition of ethanolic hydrochloric acid, suction-filtered off and washed with ethanol. Yield: 13 gm (54.8% of theory); m.p. 261°C.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][C:7]2[C:10]3[C:15]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=4)=[N:14][CH:13]=[N:12][C:11]=3[S:24][C:6]=2[CH2:5]1.[I-].[Na+].[CH3:27][O-:28].[Na+]>CN(C=O)C>[Br:23][C:19]1[CH:18]=[C:17]([NH:16][C:15]2[C:10]3[C:7]4[CH2:8][CH2:9][CH:4]([CH2:3][CH2:2][O:28][CH3:27])[CH2:5][C:6]=4[S:24][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: BrCCC1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1
Reactant: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCC1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1
Temperature: 80 °C
Yield: 43.5 %

Procedure:
To a solution of DMF were added 52 mg (0.11 mmol, 1 equiv) of N-[7-(2-bromoethyl)5,6,7,8tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]-N-(3-bromophenyl)amine, 17 mg (0.11 mmol, 1 equiv) sodium iodide, and 18 mg (0.33 mmol, 3 equiv) sodium methoxide. The solution was heated at 80° C. for 2 h and upon cooling the solution was purified by prep HPLC (10–90% ACN-H2O). The resulting pure fractions were made basic in aqueous saturated sodium bicarbonate and extracted into EtOAc (10 mL). The EtOAc layer was washed with water (1×10 mL) and dried over MgSO4. The solution was evaporated under reduced pressure yielding 20 mg (44%) of desired product, 90, as a white solid. 1H-NMR (CDCl3-d) δ 8.52 (s, 1H), 7.94 (m, 1H), 7.59 (m, 1H), 7.24 (m, 2H), 7.13 (s, 1H), 3.55 (t, 2H), 3.39 (s, 3H), 3.12 (m, 2H), 3.01 (m, 1H), 2.56 (m, 1H), 2.13 (m, 2H), 1.74 (m, 3H); TLC Rf=0.75 (9:1 CH2Cl2/MeOH); LCMS RT=3.57 min; [M+H]+=418.2.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]=[O:16])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Li][CH2:20][CH2:21][CH2:22][CH3:23]>C1COCC1>[F:18][C:2]([F:17])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([CH:15]([OH:16])[CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: [Li]CCCC
Reactant: O=Cc1cccc(-c2ccc(C(F)(F)F)cc2)n1
Solvent: C1CCOC1
Product: CCCCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 6-[4-(trifluoromethyl)phenyl]-2-pyridinecarbaldehyde (2.50 g, 9.95 mmol) in dry THF (100 mL) was cooled to 0° C. (ice/water bath) and treated with nBuLi (6.8 mL of a 1.6M solution in hexanes, 10.88 mmol) under nitrogen drop-wise over 20 minutes. The resulting deep red coloured solution was stirred at 0° C. for 1.5 hours and then quenched by the addition of aqueous HCl (2M, 10 mL) and allowed to warm to rt over about 20 minutes. The solvents were then removed under vacuum and the residue partitioned between EtOAc (150 mL) and saturated aqueous NaHCO3 (150 mL) and the layers separated. The aqueous was re-extracted with EtOAc (100 mL) and the combined organic layer washed with water (200 mL), brine (200 mL), dried (MgSO4), filtered and reduced to give a pale yellow foam. Purification by Biotage™ chromatography (silica) eluting with cyclohexane:EtOAc (gradient 100:1 to 0:1) afforded the title compound as a pale yellow oil (1.99 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[N:6][CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:35](OC)(=[O:38])[CH:36]=[CH2:37]>CN(C=O)C.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:8]1([C:5]2[N:6]=[CH:7][C:2]([CH:37]=[CH:36][CH:35]=[O:38])=[CH:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: Brc1ccc(-n2cccn2)nc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=CC=Cc1ccc(-n2cccn2)nc1
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 88.9 %

Procedure:
A solution of the compound from step A (450 mg, 2.01 mmol) and tri(o-tolyl)phosphine (123 mg, 0.40 mmol) in DMF (8 mL) was cooled to 0° C. and purged with nitrogen for 15 min. TEA (0.56 mL, 4.02 mmol) and methyl acrylate (0.36 mL, 4.00 mmol) were added and purging was continued for 5 min. Palladium acetate (45 mg, 0.20 mmol) was added and the flask was stoppered and heated to 120° C. for 24 h. The cooled reaction mixture was diluted with ether (50 mL) and washed with water (2×25 mL) and brine (25 mL), dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 4:1 hexane/ethyl acetate) yielded 356 mg (77%) of the title compound. MS 230 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[OH:22][CH2:23][CH2:24][O:25][C:26]1[C:33]([CH3:34])=[CH:32][C:29]([CH:30]=O)=[CH:28][C:27]=1[CH3:35]>C(O)C>[CH:13]([C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[C:18]([F:21])[CH:17]=3)[N:1]=[C:30]2[C:29]2[CH:32]=[C:33]([CH3:34])[C:26]([O:25][CH2:24][CH2:23][OH:22])=[C:27]([CH3:35])[CH:28]=2)=[CH:12][CH:11]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: CCC(C)c1ccc(NC(=O)c2cc(F)ccc2N)cc1
Solvent: CCO
Product: CCC(C)c1ccc(-n2c(-c3cc(C)c(OCCO)c(C)c3)nc3ccc(F)cc3c2=O)cc1
Temperature: 25 °C

Procedure:
Anhydrous CuCl2 (0.21 g, 1.6 mmol) was added to a solution of 2-amino-N-(4-sec-butylphenyl)-5-fluorobenzamide (0.15 g, 0.52 mmol), and 4-(2-hydroxyethoxy)-3,5-dimethyl-benzaldehyde (0.12 g, 0.63 mmol) in ethanol (30 mL). The resulting green solution was heated at reflux for 3 hours. After cooling to room temperature, the mixture was concentrated under vacuum. The residue was stirred with water (20 mL), and extracted with ethyl acetate (2×25 mL). The organic layer was separated, washed with brine, and dried over Na2SO4. The solvent was evaporated under vacuum, and the residue was purified by flash column chromatography on a Biotage (25 M silica column) using a gradient of hexane:ethyl acetate (8:2 to 5:5) mixture as eluent to afford the title compound. Yield: 0.19 g (77%). MP 70-72° C. 1H-NMR (400 MHz, CDCl3): 7.99 (m, 1H), 7.82 (m, 1H), 7.53 (m, 1H), 7.15 (m, 2H), 7.09 (d, 2H), 6.97 (s, 2H), 3.91 (m, 2H), 3.78 (m, 2H), 2.59 (m, 1H), 2.15 (s, 6H), 2.02 (t, 1H), 1.54 (m, 2H), 1.21 (d, 2H), 0.73 (t, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C@@H:10]1[CH2:14][NH:13][CH2:12][C@H:11]1[CH2:15][NH:16][C:17]([C:19]1[S:20][C:21]([Cl:24])=[CH:22][CH:23]=1)=[O:18].[N+](C1C=CC([O:34][C:35](=O)[NH:36][C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]3=[O:49])=[CH:39][C:38]=2[F:50])=CC=1)([O-])=O>>[F:50][C:38]1[CH:39]=[C:40]([N:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]2=[O:49])[CH:41]=[CH:42][C:37]=1[NH:36][C:35]([N:13]1[CH2:14][C@@H:10]([O:9][CH3:8])[C@H:11]([CH2:15][NH:16][C:17]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:18])[CH2:12]1)=[O:34]
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: CO[C@@H]1CNC[C@H]1CNC(=O)c1ccc(Cl)s1
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H]1CN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@H]1CNC(=O)c1ccc(Cl)s1

Procedure:
80.6 Using general method H, 5-chloro-thiophene-2-carboxylic acid ((3S,4S)-4-methoxy-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give (3R,4S)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-methoxy-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Pale yellow solid. MS 505.1 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:17][C:18](=O)[O:19]C2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1.C(N(CC)CC)C.Cl.[F:35][CH2:36][CH2:37][NH2:38]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]([NH:38][CH2:37][CH2:36][F:35])=[O:19])[CH:5]=[CH:6][C:7]=1[B:8]1[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]1
Reactant: NCCF
Reactant: CC1(C)OB(c2ccc(NC(=O)Oc3ccccc3)cc2F)OC1(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(NC(=O)NCCF)cc2F)OC1(C)C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirring solution of phenyl (3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (intermediate 30) (1.6 g, 4.48 mmol) in dry DMF was added triethylamine (2.03 mL, 14.55 mmol) and 2-fluoroethanamine hydrochloride (2.23 g, 22.40 mmol). The mixture was stirred at 50° C. for 2 h. The solvent was then removed in vacuo affording the title compound which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[CH2:19])[CH:16]=3)[O:11][C:10](=[O:20])[CH:9]=2)[CH2:3][CH2:2]1.[O:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH:31]=O)=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1>>[O:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][N:1]3[CH2:6][CH2:5][CH:4]([NH:7][C:8]4[C:17]5[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[CH2:19])[CH:16]=5)[O:11][C:10](=[O:20])[CH:9]=4)[CH2:3][CH2:2]3)=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: C=Cc1ccc2oc(=O)cc(NC3CCNCC3)c2c1
Product: C=Cc1ccc2oc(=O)cc(NC3CCN(Cc4ccc5c(c4)OCCO5)CC3)c2c1

Procedure:
4-(Piperidin-4-ylamino)-6-vinyl-chromen-2-one and 2,3-dihydro-benzo{1,4}dioxine-6-carbaldehyde were allowed to react in a manner analogous to that previously described to give the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 1.64 (m, 2H) 1.92 (m, 2H) 2.08 (m, 2H) 2.83 (m, 2H) 3.38 (s, 2H) 3.49 (m, 1H) 4.22 (m, 4H) 5.23 (s, 1H) 5.34 (m, 1H) 5.95 (m, 1H) 6.77 (m, 4H) 7.25 (m, 2H) 7.69 (m, 1H) 8.21 (m, 1H); MS (DCI/NH3) m/z 418 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][CH:9]([CH2:12][OH:13])[CH2:10][O:11][C:3]=12.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:13][CH2:12][C@H:9]1[O:8][C:4]2=[N:5][CH:6]=[CH:7][C:2]([Br:1])=[C:3]2[O:11][CH2:10]1)(=[O:24])=[O:23]
Reactant: OCC1COc2c(Br)ccnc2O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1COc2c(Br)ccnc2O1
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To a mixture of intermediate (42) (0.0014 mol) and triethylamine (0.0028 mol) in DCM (5 ml), methanesulfonyl chloride (0.0021 mol) was slowly added at room temperature. The reaction mixture was stirred for 16 hours and was then extracted with water. The separated organic layer was dried, filtered and the solvent was evaporated, yielding 0.42 g of (S)-8-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-3-methanol methanesulfonate (ester) (intermediate (43).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH2:36][CH2:37][CH2:38][OH:39]>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:36][CH2:37][CH2:38][OH:39])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: NCCO
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(NCCO)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 290 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (250 mg, 0.464 mmol) and 2-aminoethanol (142 mg, 2.31 mmol), the title compound was obtained as a white solid (110 mg, 39%). MS (ESI): 564 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[C:14]([NH:24][CH3:25])=[CH:13][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][C:35]([F:53])([F:52])[C:36]1[CH:37]=[C:38]([C:46]([CH3:51])([CH3:50])[C:47](Cl)=[O:48])[CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1>ClCCl.C(N(C(C)C)C(C)C)C>[CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[C:14]([N:24]([C:47](=[O:48])[C:46]([C:38]2[CH:37]=[C:36]([C:35]([F:34])([F:52])[F:53])[CH:41]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:39]=2)([CH3:51])[CH3:50])[CH3:25])=[CH:13][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1cnc(N(Cc2ccccc2)C(=O)OCc2ccccc2)cc1-c1ccccc1C
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(N(Cc2ccccc2)C(=O)OCc2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
To a solution of 1.075 g (2.5 mmol) benzyl-(5-methylamino-4-o-tolyl-pyridin-2-yl)-carbamic acid benzyl ester in 10 ml dichloromethane and 1 ml N-ethyldiisopropylamine was added dropwise at 0° C. a solution of 1.15 g (3.5 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionic acid chloride in 2 ml dichloromethane and the mixture was stirred for 3 h at room temperature. The solution was washed with water (20 ml), saturated aqueous sodium hydrogencarbonate solution (20 ml) and brine (20 ml), dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 1.15 g (62%) of the title compound as a yellow oil. MS m/e (%): 720 (M+H+, 100).
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:17])[CH2:6][C:7]1[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[C:9]([O:10][CH3:11])[CH:8]=1)C.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH3:2][O:4][C:5]([C:6](=[C:23]1[CH2:22][CH2:21][CH2:20][N:18]1[CH3:19])[C:7]1[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[C:9]([O:10][CH3:11])[CH:8]=1)=[O:17]
Reactant: CCOC(=O)Cc1ccc(OC)c(OC)c1
Reactant: c1ccncc1
Agent: [Na]
Solvent: CO
Product: COC(=O)C(=C1CCCN1C)c1ccc(OC)c(OC)c1

Procedure:
Add a solution of 0.46 g of sodium in 5 ml of methanol dropwise to a mixture of 5.8 g of the title compound of Example 11 and 4.5 g of homoveratric acid ethyl ester in 15 ml of pyridine. Stir the resulting reaction mixture for 2 hours at 60°, and then distil pyridine and alcohol off under a vacuum before extracting the oily residue first with water and subsequently with petroleum ether. Chromatograph thus-extracted residue on a silica gel column with chloroform/methanol (19:1) to obtain eluate with an RF value 0.76. Concentrate the eluate to obtain a yield (10.5% of theory) of the title compound in the form of an oil.
Reaction SMILES: Cl.C(N(CC)CC)C.[N-:9]=[N+:10]=[N-:11].[Na+].[C:13]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[O:18])#[N:14]>CN1CCCC1=O>[NH:9]1[C:13]([C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH:17]=[O:18])=[N:14][N:11]=[N:10]1
Reactant: N#Cc1ccccc1C=O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=Cc1ccccc1-c1nnn[nH]1
Temperature: 110 °C

Procedure:
20.3 g (147 mmol) of triethylamine hydrochloride and 21.0 g (322 mmol) of sodium azide are added to a solution of 14.0 g (107 mmol) of 2-cyano-benzaldehyde in 350 ml of 1-methyl-2-pyrrolidone and heated at 110° C. for 3 hours (argon atmosphere). The black reaction solution is poured into 0.6 liter of ice/37% HCl (20:1) and stirred thoroughly to complete the reaction. Extraction with 3 portions of ethyl acetate, washing the organic phases with 3× water and brine, drying (Na2SO4), concentration by evaporation and stirring in diethyl ether yield 2-(tetrazol-5-yl)-benzaldehyde; m.p. 130° C.; TLC: Rf=0.10 (CHCl3/methano/H2O/acetic acid=85:13:1.5:0.5).
Reaction SMILES: CC(C)([O-])C.[K+].C1COCC1.[CH3:12][O:13][C:14](=[O:35])[CH2:15][O:16][CH:17]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:18][C:19]1[C:20]([C:25](OC)=[O:26])=[N:21][CH:22]=[CH:23][CH:24]=1>C1(C)C(C)=CC=CC=1>[OH:26][C:25]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][CH:17]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:16][C:15]=1[C:14]([O:13][CH3:12])=[O:35]
Reactant: COC(=O)COC(Cc1cccnc1C(=O)OC)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1C
Product: COC(=O)C1=C(O)c2ncccc2CC(c2ccccc2)O1
Temperature: 82 °C

Procedure:
A solution of potassium tert-butoxide in THF (1M, 10 mL, 10 mmol), was added dropwise to a solution of methyl 3-(2-(2-methoxy-2-oxoethoxy)-2-phenylethyl)picolinate (3.0 g, 9.1 mmol) in xylene (20 mL) at 28° C. The resulting mixture was heated at 82° C. for 2 h, then cooled and concentrated. The residue was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 40% ethyl acetate in petroleum ether to give the title compound. MS: m/z=298.2 (M+1).