Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][CH2:2][CH2:3][OH:4].N1C=CN=C1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>ClCCl>[I:1][CH2:2][CH2:3][O:4][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCI
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCI
Reaction time: 17 h

Procedure:
To a stirred solution of 2-iodoethanol (17.2 g; 100 mmol) and imidazole (8.17 g; 120 mmol) in dichloromethane (100 mL) was added tert-butyldimethylsilyl chloride (15.83 g; 105 mmol) at such a rate that the reaction temperature did not rise above 30° C. Upon complete addition the solution was left stirring for 17 h, then washed with water (2×50 mL) and brine (50 mL) and dried over MgSO4. Evaporation of the solvent afforded the target compound (28.0 g; 97.8 mmol; 98%) as a colourless liquid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.[CH2:17]([O:19][C:20]([C:22]1[C:23](=[O:45])[C:24]2[CH:29]=[N:28][C:27](S(C)(=O)=O)=[N:26][C:25]=2[N:34]([C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[CH2:41][CH2:40][CH2:39]3)[CH:35]=1)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[C:23](=[O:45])[C:24]2[CH:29]=[N:28][C:27]([NH:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:15][CH:14]=3)=[N:26][C:25]=2[N:34]([C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[CH2:41][CH2:40][CH2:39]3)[CH:35]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: CN1CCN(CCc2ccc(N)cc2)CC1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CCN4CCN(C)CC4)cc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamine (53 mg, 0.24 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a yellow solid (70 mg, 53%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.28 (s, 1H), 8.46 (s, 1H), 7.60 (br, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.21 (s, 1H), 7.16 (br, 2H), 7.12 (d, J=7.9 Hz, 1H), 6.86 (br, 2H), 4.30 (q, J=7.1 Hz, 2H), 2.99 (t, J=7.4 Hz, 2H), 2.93 (t, J=7.4 Hz, 2H), 2.64 (n, 2H), 2.47 (m, 10H), 2.34 (s, 3H), 2.16 (m, 2H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[C:14]([Cl:15])=[C:13]([Cl:16])[C:12]([Cl:17])=[C:11]([Cl:18])[C:7]=1[C:8](O)=[O:9])=[O:5].[CH3:28][N:29]([CH3:39])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]([CH3:38])[CH3:37])[CH:31]=1.C(OC(=O)C)(=O)C.Cl>O>[CH3:37][N:36]([CH3:38])[C:32]1[CH:31]=[C:30]([N:29]([CH3:39])[CH3:28])[CH:35]=[CH:34][C:33]=1[C:4]1([C:3]2[CH:19]=[CH:20][C:21]([N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])=[CH:22][C:2]=2[CH3:1])[C:6]2[C:7](=[C:11]([Cl:18])[C:12]([Cl:17])=[C:13]([Cl:16])[C:14]=2[Cl:15])[C:8](=[O:9])[O:5]1
Reactant: CCN(CC)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c(C)c1
Reactant: CN(C)c1cccc(N(C)C)c1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCN(CC)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(C)c1
Temperature: 95 °C

Procedure:
A mixture of 2-(2-methyl-4-(diethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (22.4 g.), N,N,N',N'-tetramethyl-m-phenylenediamine (8.20 g.) and acetic anhydride (75 g.) was heated (to 95° C.) during one to two hours, then refluxed with dilute hydrochloric acid (32 g. concentrated hydrochloric acid plus 160 ml. water) during one and one-half hours. The resulting mixture was poured into water and the pH was adjusted. Recrystallization of the resulting product from toluene afforded 3-(2,4-bis(dimethylamino)phenyl)-3-(2-methyl-4-(diethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X= (CH3)2N, Y2 = CH3, Y4 = (CH3CH2)2N, Z4 = Z5 = Z6 = Z7 = Cl) (m.p. 236°-238° C.; after slurrying in acetone, 237°-239° C.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:26]
Reactant: O=C(Cl)c1ccccc1F
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccccc1F
Yield: 83.5 %

Procedure:
0.5 g (0.0026 mol) of 1-benzyl-4-hydroxypiperidine and 0.64 ml (0.0046.mol). of triethylamine were dissolved in 20 ml of toluene and treated with 0.32 ml (0.0027 mol) of 2-fluoro-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:1). 0.68 g (83%) of 1-benzyl-piperidin-4-yl 2-fluoro-benzoate was obtained as a colorless oil.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].N1CCCC1.[N:13]1([C:19]2[C:20]3[N:28]=[C:27]([CH:29]=O)[CH:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CO>[N:13]1([C:19]2[C:20]3[N:28]=[C:27](/[CH:29]=[C:5]4/[C:4](=[O:6])[NH:3][C:2](=[O:7])[S:1]/4)[CH:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc2ncnc(N3CCCCC3)c2n1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1NC(=O)/C(=C/c2ccc3ncnc(N4CCCCC4)c3n2)S1
Temperature: 70 °C
Yield: 48.8 %

Procedure:
A mixture of 2,4-thiazolidinedione (3.4 g; 29.1 mmol; 1.80 eq.), pyrrolidine (269.80 μL; 3.2 mmol; 0.2 eq.) in MeOH (50 mL) was heated at 70° C. A solution of 4-(1-piperidinyl)pyrido[3,2-d]pyrimidine-6-carbaldehyde (Intermediate 1.7) (3.9 g; 16.2 mmol; 1 eq.) in MeOH (50 mL) was slowly added over 1.5 hour at 70° C. After 2 h under reflux after the addition, the reaction was complete. A precipitate was formed. The hot reaction mixture was filtered and the solid was washed with cold MeOH to give (5Z)-5-{[4-(1-piperidinyl)pyrido[3,2-d]pyrimidin-6-yl]methylene}-1,3-thiazolidine-2,4-dione (1) (2.70 g; 48%) as an orange powder in 98% HPLC purity.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[CH3:13][CH2:14][OH:15]>O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:14]1[C:13]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[O:15]1
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: CCO
Solvent: O
Product: O=C1OC(c2c(O)c3ccccc3oc2=O)c2ccccc21
Temperature: 25 °C

Procedure:
A solution of 4-hydroxy-chromen-2-one (650 mg) and 2-carboxybenzyladehyde (300 mg) in EtOH was heated to reflux for 4 hours, cooled to room temperature then concentrated in vacuo to give a crude oil, which was diluted with water. The precipitated 4-hydroxy-chromen-2-one was collected by filtration (490 mg). A second crop of solid was collected from the mother liquor and triturated with hot EtOAc and filtered to provide 4-Hydroxy-3-(3-oxo-1,3-dihydro-isobenzofuran-1-yl)-chromen-2-one as white solid. MS: 293 [M−H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20].N12CCCN=C1CCCCC2>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCBr
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)CCn1ccc(OCc2ccccc2)cc1=O
Temperature: 25 °C
Yield: 42.3 %

Procedure:
A solution of 4-benzyloxy-1H-pyridin-2-one (1.0 g, 4.97 mmol) and 1-bromo-3-methyl butane (0.715 mL, 5.96 mmol) in N,N-dimethylformamide (20 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.86 mL, 12.43 mmol) at 65° C. for 5 days. The mixture was cooled to 25° C. and partitioned between water and dichloromethane. The organic layer was concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 1% methanol in dichloromethane to give the title compound (0.57 g, 42%). MS (DCI/NH3) m/z 272 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 0.96 (d, J=6.25 Hz, 6 H) 1.61 (m, 3 H) 3.89 (m, 2 H) 4.99 (s, 2 H) 5.98 (dd, J=7.54, 2.76 Hz, 1 H) 6.06 (d, J=1.84 Hz, 1 H) 7.14 (d, J=7.72 Hz, 1 H) 7.39 (m, 5 H).
Reaction SMILES: Cl[CH:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][C:4]([F:8])=[C:5]([F:7])[F:6].C([SnH](CCCC)CCCC)CCC>>[F:6][C:5]([F:7])=[C:4]([F:8])[CH2:3][CH2:2][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCC(Cl)CC(F)=C(F)F
Agent: CCCC[SnH](CCCC)CCCC
Product: CCCCCCCCCCC(F)=C(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred mixture of 4.6 grams (0.0179 mole) of 4-chloro-1,1,2-trifluoro-1-dodecene (prepared as in Example 7) and 0.04 gram (0.0003 mole) of alpha, alpha-azobisisobutyronitrile is flushed with argon and 5.1 ml (0.019 mole) of tri-n-butyltin hydride is added dropwise. Upon completion of addition, the reaction mixture is stirred at ambient temperature for 16 hours. The reaction mixture is fractionally distilled under reduced pressure through a Vigreux column. The appropriate fractions are recombined and redistilled, again under reduced pressure and through a Vigreux column. The yield of 1,1,2-trifluoro-1-dodecene is 1.2 grams; b.p. 42°-45° C./0.45 mm. The nmr spectrum is consistent with the proposed structure. Analysis: calc'd for C12H21F3 : C 64.85, H 9.52; Found: C 64.82, H 9.32.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH3:14]>>[NH2:14][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Reactant: N
Product: Nc1nc2ccc([N+](=O)[O-])cc2s1

Procedure:
Various processes for the preparation of 2-amino-6-nitrobenzothiazole are known. For example Pubbl. ist. chim. univ. Bologna No. 2, 3-10 (1943); Chemical Abstracts 41:754 discloses the chlorination of 2-mercaptobenzothiazole to give 2-chlorobenzothiazole which is then treated with nitric and sulfuric acids to give 2-chloro-6-nitrobenzothiazole. The 2-chloro-6-nitrobenzothiazole is then treated with alcoholic ammonia under pressure at 140° to give 2-amino-6-nitrobenzothiazole. No yields are stated in the English abstract.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[N:31]=[C:32]=[O:33])([CH3:21])[CH3:20]>>[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:29])[CH3:30])[C:23]=1[NH:31][C:32](=[O:33])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:18])[CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)([CH3:20])[CH3:21]
Reactant: Cc1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: Cc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 1 using [(4-dimethylaminophenyl)methyl](4-methylphenyl)amine (0.70 g) and 2,6-diisopropylphenyl isocyanate (0.69 mL) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]-N-(4-methylphenyl)urea (0.41 g) was obtained. melting point: 124–125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:13][CH2:12][CH2:11][CH2:10][C:9]#[C:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: OCCCC#Cc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCC#Cc2ccc(Cl)cc2)cc1
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
5-(4-Chlorophenyl)pent-4-yn-1-ol (35.7 g, 182 mmol), 4-dimethylaminopyridine (8.9 g, 73 mmol), p-toluenesulfonyl chloride (34.7 g, 182 mmol), and 62 ml of triethylamine were combined in 330 ml of dichloromethane at 0° C. The mixture was stirred for 30 min. at 0° then 18 hours at room temperature. Dilution with 200 ml of dichloromethane followed by washing with brine, drying over magnesium sulfate, filtration through silica gel with hexane-ethyl acetate, 8:1, gave a yellow solid on evaporation. Crystallization from ether gave 5-(4-Chlorophenyl)pent-4-yn-1-ol p-toluenesulfonate as colorless crystals (31.7 g, 49% yield). This was converted to the title compound by reaction with sodium iodide in acetone, and was used in subsequent reactions with no further purification; MS m/z 303.9 (M+ calcd. for C11H10ClI=304.6).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][C:11](O)=[C:6]2[CH:5]=[N:4]1)[CH3:2].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:11]1[CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=12
Reactant: CCn1ncc2c(O)cc(-c3ccccc3)nc21
Reactant: O=P(Cl)(Cl)Cl
Product: CCn1ncc2c(Cl)cc(-c3ccccc3)nc21

Procedure:
A mixture of 193.9 gms. of 1-ethyl-4-hydroxy-6-phenyl-1H-pyrazolo[3,4-b]pyridine (0.7 mol.) and 1000 ml. of phosphorus oxychloride is refluxed for 5 hours. The excess phosphorus oxychloride is removed in vacuo and the residue is treated with ice water. The mixture is then extracted three times with ether, the ether layer is separated, dried over sodium sulfate, treated with charcoal and concentrated in vacuo. The residue solidifies on cooling (142.4 gms = 79%; m.p. 43°-45° C.) and the product, 4-chloro-1-ethyl-6-phenyl-1H-pyrazolo[3,4-b]pyridine is recrystallized from hexane, m.p. 46°-48° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18](=[O:20])[N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Br)cc2)nc2cccnc21)N1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.0 g, 0.018 mole), 1,1'-carbonyldiimidazole (3.1 g, 0.019 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through for 3 hours. The nitrogen flow was stopped and a solution of piperidine (1.7 g, 0.020 mole) in dry tetrahydrofuran (25 ml) was added. The solution was stirred at room temperature under nitrogen for 2 hours. The reaction mixture was concentrated in vacuo and the residue triturated in potassium bicarbonate solution (100 ml) and filtered. The filter cake was washed with water and recrystallized from isopropyl alcohol-isopropyl ether to give 5.9 g (82%) of white flakes, mp 175°-176° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH2:12]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@@H:24]([O:27][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(C(=O)OCc3ccccc3)C2)cc1
Reaction time: 48 h

Procedure:
22.25 g (0.117 moles) of toluene-4-sulfonyl chloride, dissolved in 30 ml of pyridine, were added dropwise to a stirred solution of 11.79 g (0.053 moles) of (3R)-N-benzyloxycarbonyl-3-hydroxypyrrolidine [J. Chem. Soc., Chem. Commun. 1984, 1298]in 50 ml of pyridine, cooled below 0° C. After the addition, the reaction mixture was kept at 5° C. for 48 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[SH:26][CH2:27][CH2:28][OH:29]>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][S:26][CH2:27][CH2:28][OH:29])=[CH:4][CH:3]=1
Reactant: OCCS
Reactant: Clc1ccc(C(OCCBr)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: OCCSCCOC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 18 h
Yield: 97.2 %

Procedure:
A solution of 2-[bis(4-chlorophenyl)methoxy]ethyl bromide (5.13 g, 14.2 mmol) in N,N-dimethylformamide (50 ml) was treated at 22° C. with powdered anhydrous potassium carbonate (3.0 g, 21.7 mmol) followed by 2-mercaptoethanol (1.25 g, 16.0 mmol). The resulting mixture was stirred at 22° for 18 h. The reaction mixture was then diluted with toluene (400 ml) washed with water, brine and dried over magnesium sulfate. Evaporation of the solvent gave an oil which was chromatographed on silica gel (elution ethyl acetate 0-10% in toluene) to give 4.93 g (96%) of the title material as a clear oil.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]2[C:25]3[NH:24][C:23]4[CH2:26][CH2:27][NH:28][CH2:29][C:22]=4[C:21]=3[CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1>C(O)(=O)C>[C:5]([N:28]1[CH2:27][CH2:26][C:23]2[NH:24][C:25]3[C:17](/[CH:16]=[CH:15]/[C:12]4[CH:13]=[N:14][C:9]([CH3:8])=[CH:10][CH:11]=4)=[CH:18][CH:19]=[CH:20][C:21]=3[C:22]=2[CH2:29]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(/C=C/c2cccc3c4c([nH]c23)CCNC4)cn1
Solvent: CC(=O)O
Product: CC(=O)N1CCc2[nH]c3c(/C=C/c4ccc(C)nc4)cccc3c2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Acetic anhydride (1 mL; Fischer) was added dropwise to a solution of the product of Example 6C (45 mg, 0.16 mmol) in acetic acid (1 mL). The reaction mixture was stirred at room temperature for 10 minutes and then concentrated under vacuum. The resulting residue was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (400 MHz, methanol-d4) (1:1 mixture of amide rotamers observed) δ ppm 2.23 and 2.24 (two s, 3H; amide rotamers), 2.54 (s, 3H), 2.90 and 2.99 (two t, J=5.8 Hz, 2H; amide rotamers), 3.91 and 3.99 (two t, J=5.8 Hz, 2H; amide rotamers), 4.74-4.77 (m, 2H), 7.05 and 7.06 (two t, J=7.6 Hz, 2H; amide rotamers), 7.24 (d, J=16.5 Hz, 1H), 7.31 (d, J=8.2 Hz, 1H), 7.36 and 7.39 (two dd, J=7.8, 0.8 Hz, 1H; amide rotamers), 7.42 and 7.43 (two d, J=7.3 Hz, 1H), 7.67 (d, J=16.5 Hz, 1H), 8.00 and 8.02 (two t, J=1.8 Hz, 1H), 8.61 (d, J=2.1 Hz, 1H); MS (APCI) m/z 332 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([F:16])=[C:13]([OH:15])[CH:14]=2)=[N:6][CH:7]=1.Br[CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([F:16])=[C:13]([CH:14]=2)[O:15][CH2:18][CH2:19][OH:20])=[N:4][CH:3]=1
Reactant: OCCBr
Reactant: Oc1cc(Nc2ncc(Br)cn2)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: OCCOc1cc(Nc2ncc(Br)cn2)ccc1F

Procedure:
A solution of 5-(5-bromopyrimidin-2-ylamino)-2-fluorophenol 45 (0.25 mmol), 2-bromoethanol (0.28 mmol) and cesium carbonate (0.36 mmol) in acetonitrile (3 mL) is heated to 100° C. for 12 h. The reaction is evaporated to dryness then re-dissolved in DCM. The organic mixture is washed with water and brine then dried over magnesium sulfate, filtered and reduced to dryness to yield 2-(5-(5-bromopyrimidin-2-ylamino)-2-fluorophenoxy)ethanol 46a as a brown solid which is used without further purification. MS (m/z) (M+1)+: 329.2.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[O:6][CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>ClCCl>[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[O:6][CH2:5][CH2:4]1)=[O:30]
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CCO2
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
(R)-Methyl 4-aminochromane-6-carboxylate hydrochloride (A-03) (0.6 g, 2.462 mmol, 1.0 eq) was dissolved in dichloromethane and DIPEA (2.5 eq) under nitrogen, and 2-chlorobenzoic acid chloride (0.37 ml, 2.954 mmol, 1.2 eq) was added at 0° C. The reaction mixture was stirred for 3 h at RT. Then the reaction mixture was concentrated, and the residue was taken up in ethyl acetate, washed with 10% ammonium chloride solution, sat. NaHCO3 solution and with sat. NaCl solution, dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, cyclohexane:ethyl acetate 2:1) to yield (R)-methyl 4-(2-chlorobenzamido)chromane-6-carboxylate (B-05). Yield: 92%
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.[OH-].[Li+]>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Sc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccc(Cl)cc2)nc1
Temperature: 0 °C

Procedure:
6-Chloro-3-nitropyridine (54.5 grams), 4-chlorothiophenol (50.0 grams), and lithium hydroxide (12.5 grams) were mixed in about 500 ml. of DMF and stirred overnight (about 18 hours) at room temperature. The reaction mixture was poured into ice-water, filtered, and the separated product washed three times with water and air dried, yield, 100 grams.
Reaction SMILES: CN(C)[CH:3]=[O:4].[O:6]=[C:7]([CH3:14])[CH2:8][CH2:9][CH2:10][C:11](O)=[O:12].C(=O)([O-])[O-].[K+].[K+].CI>O>[O:6]=[C:7]([CH3:14])[CH2:8][CH2:9][CH2:10][C:11]([O:4][CH3:3])=[O:12]
Reactant: CC(=O)CCCC(=O)O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)CCCC(C)=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To 80 ml of N,N-dimethylformamide, 25 g (0.19 mol) of 5-oxohexanoic acid and 43 g (0.31 mol) of potassium carbonate were dissolved and heated at 50° C., followed by drop-wisely adding 41 g (0.29 mol) of methyl iodide and stirring at the same temperature for 2 hours. To this mixture, 150 ml of water was added, followed by extracting with diethyl ether (200 ml×4). The organic layer was washed with a saturated saline solution, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure to obtain 24.9 g (yield: 90%) of methyl 5-oxohexanoate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]#[C:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]#[C:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCC#Cc1ccc(C(=O)O)cc1
Reaction time: 5 h
Yield: 5.7 %

Procedure:
Methyl 4-(3-t-butoxycarbonylaminoprop-1-ynyl)benzoate (1.09 g, 38 mmol, reference example 81) is dissolved in MeOH (15 mL) and to this solution added NaOH (0.15 g, 38 mmol) dissolved in water (5 mL). This mixture is heated to reflux. After 5 hours, the solvent is removed in vacuo and CH2Cl2 and 1N HCl added to the residue. The organic layer is washed with 1N HCl, water and brine, then dried over magnesium sulfate. The solvent is removed in vacuo to give a white solid (0.60 g, 57% yield): 1H NMR (300 MHz, CD3OD) d 7.86 (d, 2H), 7.39 (d, 2H), 3.98 (s, 2H), 1.38 (s, 9H).