Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[C:2]#[CH:3].[CH2:11]([Li])CCC.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.[Cl-].[NH4+]>C1COCC1.CCCCCC>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:25])[C:11]#[C:3][CH2:2][CH2:1][O:4][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][O:6]2)=[CH:19][CH:18]=1
Reactant: C#CCOC1CCCCO1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(C#CCCOC1CCCCO1)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.8 %

Procedure:
To a solution of 4.98 g (35.5 mmol) of tetrahydro-2-(2-propynyloxy)-2H-pyran in 70 mL of THF under N2 was added 14.2 mL (35.5 mmol) of 2.5 M n-butyllithium in hexane. After 15 minutes, 7.03 g (35.5 mmol) of 4-bromophenylisocyanate was added and then the reaction was allowed to warm to room temperature. Saturated aqueous ammonium chloride (20 mL) was added and the mixture extracted with 30 mL ethyl acetate three times. The combined organic extracts were dried with MgSO4, concentrated to an oil in vacuo and then chromatographed on silica with 20% EtOAc/hexane to give 7.1 g (59%) of the desired alkyne. 1H NMR (CDCl3) δ: 7.53 (br s, 1H); 7.43 (d, 2H); 7.42 (d, 2H); 4.80 (m, 1H); 4.43 (d, 1H); 4.40 (d, 1H); 3.83 (m, 1H); 3.59 (m, 1H); 1.7 (m, 6H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[CH3:33][N:34]1[C:38]([CH2:39][NH2:40])=[CH:37][N:36]=[CH:35]1>>[CH3:33][N:34]1[C:38]([CH2:39][NH:40][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([C:11]3[O:12][C:8]([CH3:7])=[C:9]([CH2:22][S:23]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)(=[O:24])=[O:25])[N:10]=3)=[CH:14][CH:15]=2)=[CH:37][N:36]=[CH:35]1
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Reactant: Cn1cncc1CN
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4cncn4C)cc3)oc2C)cc1
Yield: 82.3 %

Procedure:
Reaction of oxalyl chloride (111 λL, 1.27 mmol) and benzoic acid 4 (318 mg, 0.85 mmol) with subsequent coupling to (1-methyl-1H-imidazol-5-yl)methylamine (104 mg, 0.94 mmol) gave benzamide 15 (325 mg, 82%) as a white powder: mp (EtOAc) 240-242° C.; 1H NMR δ 8.93 (t, J=5.3 Hz, 1H, CONH), 7.97 (br d, J=8.5 Hz, 2H, H-2, H-6), 7.87 (br d, J=8.5 Hz, 2H, H-3, H-5), 7.67 (br d, J=8.3 Hz, 2H, H-2′, H-6′), 7.54 (s, 1H, H-2″), 7.42 (br d, J=8.3 Hz, 2H, H-3′, H-5′), 6.84 (s, 1H, H-4″), 4.62 (s, 2H, CH2SO2), 4.48 (d, J=5.3 Hz, 2H, CH2N), 3.62 (s, 3H, NCH3), 2.40 (s, 3H, CH3), 2.13 (s, 3H, CH3); 13C NMR δ 165.1, 157.9, 149.8, 144.4, 138.1, 135.5, 135.4, 129.5 (2), 128.7, 128.6, 128.1 (2), 128.0 (2), 127.7, 125.9, 125.2 (2), 52.8, 32.5, 30.9, 20.9, 9.5; MS m/z 465.5 (MH+, 100%). Anal. calcd for C24H24N4O4S: C, 62.05; H, 5.21; N, 12.06. Found: C, 62.42; H, 5.24; N, 12.12%.
Reaction SMILES: C(S[C:9]1[CH2:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:11]=2[N:10]=1)C1C=CC=CC=1.O.O.[NH2:29][NH2:30]>CO.O1CCCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:11]2[N:10]=[C:9]([NH:29][NH2:30])[CH2:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]=2[CH:22]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCC(SCc1ccccc1)=N2
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reaction time: 8 h

Procedure:
Thus obtained 2-benzylmercapto-7-chloro-5-phenyl-3H-1,4-benzodiazepine (4 parts) is dissolved in 100 parts by volume of a mixture of methanol and tetrahydrofuran (1:1) and 10 parts by volume of hydrazine hydrate is added thereto. After being left standing overnight at room temperature, the reaction mixture is poured into water and extracted with chloroform. The chloroform layer is washed with water and dried over sodium sulfate. Evaporation of the solvent affords 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine. Recrystallization from a mixture of chloroform and benzene gives colorless crystals. M.P. 203°-205° C (decomposition). Thus obtained product is identical with the product prepared in Examples 1 and 9.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[F:20]C1C=CC=C2C=1NC=C2>>[F:20][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2
Reactant: Fc1cccc2cc[nH]c12
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Product: CC1(C)OB(c2cc3cccc(F)c3[nH]2)OC1(C)C

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-fluoro-1H-indole.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([O:21]C)=[O:20])=[N:15][CH:16]=3)=[C:8]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[S:7][C:6]=2[CH:30]=1.[OH-].[Li+]>C1COCC1.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[N:15][CH:16]=3)=[C:8]([C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)[S:7][C:6]=2[CH:30]=1
Reactant: COC(=O)/C=C/c1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)/C=C/c1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.7 %

Procedure:
To a solution of (E)-methyl 3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylate (0.118 g, 0.28 mmol) in THF (2.00 mL) and water (2.00 mL) was added lithium hydroxide (1.0 M aq., 0.844 mL, 0.84 mmol) and the reaction was stirred at room temperature for 2 h. Upon completion the reaction was quenched with water, diluted with DCM and acidified to pH 1 with 1 N HCl. The mixture was extracted with DCM (3×) and the combined organic layers were passed through a phase separator and concentrated in vacuo to afford the crude product which was purified by reverse phase HPLC (acidic condition, 3% TFA in 10-100% CH3CN/H2O) to afford (E)-3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylic acid (14 mg, 0.03 mmol, 9% yield). 1H NMR (400 MHz, (CD3)2SO) δ ppm=6.66 (d, J=15.66 Hz, 1H), 6.77-6.81 (m, 2H), 6.84 (dd, J=8.59, 2.02 Hz, 1H), 7.17 (d, J=8.59 Hz, 1H), 7.22 (dd, J=8.59, 3.03 Hz, 1H), 7.31 (d, J=2.02 Hz, 1H), 7.44-7.49 (m, 2H), 7.52 (d, J=15.66 Hz, 1H), 7.64 (d, J=8.59 Hz, 1H), 8.45 (d, J=2.53 Hz, 1H). LC/MS (m/z, MH+): 406.2.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:11][C:10]([N:12]=CN(C)C)=[N:9][C:8]=1[CH3:17])=O.[N+]([O-])(O)=O.[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH2:36])=[NH:35])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>CC#N>[NH2:12][C:10]1[S:11][C:7]([C:5]2[CH:4]=[CH:3][N:36]=[C:34]([NH:33][C:30]3[CH:29]=[CH:28][C:27]([S:24]([CH3:23])(=[O:25])=[O:26])=[CH:32][CH:31]=3)[N:35]=2)=[C:8]([CH3:17])[N:9]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)N)cc1
Reactant: Cc1nc(N=CN(C)C)sc1C(=O)C=CN(C)C
Solvent: O=[N+]([O-])O
Solvent: CC#N
Product: Cc1nc(N)sc1-c1ccnc(Nc2ccc(S(C)(=O)=O)cc2)n1

Procedure:
By condensation of N′-[5-(3-dimethylamino-acryloyl)-4-methyl-thiazol-2-yl]-N,N-dimethyl-formamidine and N-(4-methanesulfonyl-phenyl)-guanidine nitrate. Yellow solid. Anal. RP-HPLC: tR=13.2 min (0-60% MeCN, purity>97%). 1H-NMR (DMSO-d6) δ: 1.98 (s, 3H, CH3), 2.54 (s, 3H, CH3), 7.06 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.80 (m, 2H, Ph-H), 8.00 (m, 2H, Ph-H), 8.45 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 10.05 (sbr, 2H, NH2). MS (ESI+) m/z 362.38 [M+H]+ (C15H15N5O2S2 requires 361.44).
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:21][O:20]1>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[N:5]([CH2:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)([OH:20])[CH3:21])[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3
Reactant: CC1(c2ccccn2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccccn2)CN(C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.7 %

Procedure:
2,6-Dimethyl-2,3,4,9-tetrahydro-1H-β-carboline (500 mg, 2.5 mmol) was dissolved in 20 mL DMF and stirred for 10 min at RT. Sodium hydride (180 mg, 7.5 mmol) was added portionwise at RT and the mixture stirred for 10 min. 2-(2-Methyl-oxiranyl)-pyridine (472 mg, 3.5 mmol) was added dropwise at the same temperature and stirred for 12 h at RT. The reaction was monitored by TLC & LCMS. After consumption of starting material, the reaction mixture was quenched with ice water and extracted with EtOAc (3×100 mL). The combined organic layer was washed with water (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated and the residue was crystallized in hexane to obtain 115 mg of 1-(2,6-dimethyl-1,2,3,4-tetrahydro-β-carbolin-9-yl)-2-pyridin-2-yl-propan-2-ol. 1HNMR (CDCl3, freebase) δ (ppm): 8.51 (d, 1H), 7.65 (t, 1H), 7.29 (d, 1H), 7.22 (d, 1H), 7.20 (s, 1H), 6.95 (d, 1H), 6.85 (d, 1H), 4.9 (bs, 1H), 4.18 (s, 2H), 3.21 (dd, 2H), 2.77 (m, 2H), 2.69 (m, 2H), 2.42 (d, 6H), 1.63 (s, 3H). Separation by chiral HPLC provided enantiomers 16a and 16b. Optical rotations: Compound No. 16a, (−) 5.77 (c 0.52, Chloroform, 98.11% HPLC purity); Compound No. 16b, (+) 5.85 (c 0.51, Chloroform, 98.06% HPLC purity).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([Cl:17])[CH:3]=1.N1C=CN=C1.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25].C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][Si:27]([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28])=[CH:11][N:12]=2)=[C:4]([Cl:17])[CH:3]=1
Reactant: Cc1cc(Br)cc(Cl)c1Oc1ccc(O)cn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(Cl)c1Oc1ccc(O[Si](C)(C)C(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
To a DMF (50 mL) solution of 6-(4-bromo-2-chloro-6-methylphenoxy)pyridin-3-ol (5.00 g) were added imidazole (1.41 g) and TBDMSCl (2.87 g) at room temperature. After stirring at room temperature for 5 hours, to the reaction mixture was added saturated aqueous NaHCO3, and extracted with AcOEt. The organic layer was washed with water, saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=9/1 to 2/1) to give 2-(4-bromo-2-chloro-6-methylphenoxy)-5-{[tert-butyl(dimethyl)silyl]oxy}pyridine as a colorless oil (6.16 g).
Reaction SMILES: Br[CH:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.C(#N)C.O.CC[O:28]CC>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[Ag+].C(O)(=O)C>[CH:12]1[C:7]2[CH:6]=[CH:5][C:4]3[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=3[C:2](=[O:28])[C:8]=2[CH:9]=[CH:10][C:11]=1[CH:13]([CH3:17])[C:14]([OH:16])=[O:15]
Reactant: CC(C(=O)O)c1ccc2c(c1)C=Cc1ccccc1C2Br
Reactant: CCOCC
Agent: [Ag+]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Temperature: 120 °C
Yield: 15 %

Procedure:
1.0 Gm. of silver p-toluenesulfonate and 0.5 gm. of 2-(5-bromo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid are stirred in 50 ml. of acetonitrile in the dark for 6 hours. Water, ether and 2.0 ml. of acetic acid are added. The ethereal layer is washed, dried and evaporated. The products, 2-(5-p-toluene-sulfonyloxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid, is dissolved in 10 ml. of dimethylsulfoxide and heated to 120° C. for 5 minutes, then cooled, poured into water and extracted with ethyl acetate. The solution is washed, dried and evaporated. The residue is chromatographed on silica gel, eluting with 40:60:1 ethyl acetate: acetic acid, so as to isolate a 15% yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl propionic acid, m.p. (chloroform-hexane) 138°-139° C.; m.p. (acetone-hexane) 113°-115° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1I.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]3[C:3]=2[C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)Cn1nc2c(I)c(Br)ccn2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 200 °C
Yield: 40.8 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-iodo-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.13 mmol), 4-chlorophenylboronic acid (40 mg, 0.28 mmol), and tetrakis(triphenylphosphine)palladium (7 mg, 0.006 mmol) in dioxane (1.0 mL) at 20° C. was added K2CO3 (40 mg, 0.25 mmol) in water (0.3 mL). The resulting reaction mixture was heated in a microwave reactor at 200° C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (22 mg, 0.053 mmol) as a light yellow solid. MS: [M+H]+=412.
Reaction SMILES: [OH-].[K+].C([O:9][CH2:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:18]=[CH:19][C:20]3[C:25]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]4[CH3:32])=[N:24][C:23]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])=[N:22][C:21]=3[N:40]=2)[CH:14]=[CH:13][C:12]=1[O:41][CH3:42])(=O)C(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(Cl)Cl>C1COCC1.CO>[CH3:39][C@H:34]1[CH2:35][O:36][CH2:37][CH2:38][N:33]1[C:23]1[N:24]=[C:25]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]2[CH3:32])[C:20]2[CH:19]=[CH:18][C:17]([C:15]3[CH:14]=[CH:13][C:12]([O:41][CH3:42])=[C:11]([CH2:10][OH:9])[CH:16]=3)=[N:40][C:21]=2[N:22]=1
Reactant: COc1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1COC(=O)C(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1CO
Reaction time: 4 h
Yield: 95.2 %

Procedure:
Potassium hydroxide solution (1.7 mL, 3.10 mmol) was added to a solution of 5-{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxybenzyl pivalate (172 mg, 0.30 mmol) in THF (6.9 mL) and methanol (1.7 mL) at RT under an atmosphere of nitrogen. After 240 minutes, HPLC analysis showed complete disappearance of the starting material. The reaction was maintained at RT overnight (for convenience) and aqueous citric acid (20% w/v, 2 mL) was added followed by methylene chloride (15 mL). The upper aqueous layer was extracted with two further extractions of methylene chloride (2×15 mL) and the organic layers combined. Evaporation of the methylene chloride afforded (5-{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (6) as a yellow solid (133 mg).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([OH:14])=[C:7]([C:15](=[O:17])[CH3:16])[C:6]=1[CH3:18])(=[O:3])[CH3:2].[C:19]1(=O)[CH2:22][CH2:21][CH2:20]1.N1CCCC1>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([CH3:18])=[C:7]2[C:8](=[CH:9][C:10]=1[CH:11]([CH3:13])[CH3:12])[O:14][C:19]1([CH2:22][CH2:21][CH2:20]1)[CH2:16][C:15]2=[O:17])(=[O:3])[CH3:2]
Reactant: O=C1CCC1
Reactant: CC(=O)Oc1c(C(C)C)cc(O)c(C(C)=O)c1C
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CC(=O)Oc1c(C(C)C)cc2c(c1C)C(=O)CC1(CCC1)O2
Reaction time: 16 h
Yield: 39 %

Procedure:
To a solution of 3-acetyl-4-hydroxy-6-isopropyl-2-methylphenyl acetate (8.5 g) and cyclobutanone (2.6 g) in toluene (150 mL) was added pyrrolidine (1.2 g). The solution was left at room temperature for 16 hours, refluxed for two hours, and then a Dean-Stark was used to remove the water. Work up and chromatography (silica gel, hexane-ethyl acetate 2% to 5%) gave 4 g of 7-isopropyl-5-methyl-4-oxospiro[chroman-2,1′-cyclobutane]-6-yl acetate.
Reaction SMILES: C(=O)=O.C(Cl)(Cl)(Cl)Cl.[Cl:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[O:12].N(CCO)CCO>C1COCC1>[Cl:9][CH2:10][C@@H:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[OH:12]
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: O=C=O
Solvent: OCCNCCO
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: O[C@@H](CCl)c1ccc(Cl)cc1Cl
Temperature: -25 °C
Reaction time: 7 h
Yield: 112 %

Procedure:
To a solution containing 16 g (49.90 mmol) of (−)-DIP-Cl in 30 mL of anhydrous THF, at −25° C. (dry ice, CCl4), under nitrogen, was added 10 g (44.74 mmol) of 2,2′,4′-trichloroacetophenone. The stoppered solution was stirred at −25° C. for about 7 hours, and then at room temperature overnight. THF was removed in vacuo, and (+)-α-pinene was removed under high vacuum at room temperature overnight. The resulting viscous colorless oil was dissolved in 200 mL of anhydrous ether, and cooled to 0° C. Diethanolamine (10.50 g, 0.10 mol) was added to the filtrate, and stirring was continued for 3 hours at room temperature. The white solid obtained was removed by filtration and washed with anhydrous ether. The colorless solution was evaporated to dryness to yield a viscous colorless oil. This oil was flash chromatographed on silica gel, first with hexanes to remove (+)-α-pinene. The product was eluted from the column with 93% hexanes/7% acetone to yield 11.30 g of a white solid. This solid was crystallized from hexanes at 0° C. Yield: 5.75 g (57%); TLC: 95% hexanes/5% acetone, Rf=0.10.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]2([C:32]([F:35])([F:34])[F:33])[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]([NH:26][C:27]([CH:29]4[CH2:31][CH2:30]4)=[O:28])[CH3:25])=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.I(C1C=CC=CC=1)=[O:39]>ClCCl>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2([C:32]([F:35])([F:34])[F:33])[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[CH:20][C:21]([C@@H:24]([NH:26][C:27]([CH:29]4[CH2:31][CH2:30]4)=[O:28])[CH3:25])=[CH:22][CH:23]=3)[CH:14]2[OH:39])[CH:4]=[C:3]([C:2]([F:36])([F:1])[F:37])[CH:8]=1
Reactant: O=Ic1ccccc1
Reactant: C[C@H](NC(=O)C1CC1)c1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Solvent: ClCCl
Product: C[C@H](NC(=O)C1CC1)c1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 11.7 %

Procedure:
N-[(1S)-1-(4-{3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl)phenyl)-ethyl]cyclopropanecarboxamide (cf. Japanese Patent Application No. 2009-296889) (200 mg) was dissolved in dichloromethane (10 mL), and to the reaction solution was added Fe(salen) (12 mg) and iodosobenzene (98 mg). The resulting mixture was stirred at room temperature for 20 hours. Under reduced pressure, the solvent was distilled off and the residues were purified by silica gel column chromatography to obtain N-[(1S)-1-(4-{3-[3,5-bis(trifluoromethyl)-phenyl]-2-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl}phenyl)ethyl]cyclopropane-carboxamide (24 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:22]1[CH2:26][CH:25]([CH2:27][CH3:28])[CH:24]=[N:23]1)=[N:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][N:15]2C(=O)C)=[CH:11][C:10]=1[Br:21])(=[O:8])=[O:7])[CH3:2].Cl.C([O-])(O)=O.[Na+]>CO>[CH2:1]([NH:3][C:4]([N:22]1[CH2:26][CH:25]([CH2:27][CH3:28])[CH:24]=[N:23]1)=[N:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][NH:15]2)=[CH:11][C:10]=1[Br:21])(=[O:8])=[O:7])[CH3:2]
Reactant: CCNC(=NS(=O)(=O)c1cc2c(cc1Br)CCN2C(C)=O)N1CC(CC)C=N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCNC(=NS(=O)(=O)c1cc2c(cc1Br)CCN2)N1CC(CC)C=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
0.65 g 1-Acetyl-5-bromo-2,3-dihydro-1H-indole-6-sulfonic acid ethylamino-(4-ethyl-4,5-dihydro-pyrazol-1-yl)-methyleneamide was dissolved in 20 mL MeOH and 20.7 mL of 1M HCl in MeOH was added. The mixture was stirred overnight under reflux. After cooling to room temperature, the mixture was basified with a 5% NaHCO3 solution and extracted twice with DCM. The combined organic layers were dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (DCM/EA 9:1→8:2) to give 0.35 g (64%) of 5-Bromo-2,3-dihydro-1H-indole-6-sulfonic acid ethylamino-(4-ethyl-4,5-dihydro-pyrazol-1-yl)-methyleneamide as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 0.96 (t, J=7.37 Hz, 3H), 1.17 (t, J=7.22 Hz, 3H), 1.45-1.68 (m, 2H), 3.00-3.15 (m, 3H), 3.48-3.57 (m, 2H), 3.62 (t, J=8.43 Hz, 2H), 3.71 (dd, J=11.14, 7.52 Hz, 1H), 3.91 (br.s., 1H), 4.08-4.17 (m, 1H), 6.76 (br.s., 1H), 6.90 (d, J=1.50 Hz, 1H), 7.34 (s, 1H), 7.46 (s, 1H).
Reaction SMILES: [CH:1]#[C:2][CH3:3].[Cl:4][C:5]1[CH:6]=[C:7](I)[C:8]([NH2:11])=[N:9][CH:10]=1.C(N(CC)CC)C>C1COCC1.[Cu]I>[Cl:4][C:5]1[CH:6]=[C:7]([C:1]#[C:2][CH3:3])[C:8]([NH2:11])=[N:9][CH:10]=1
Reactant: Nc1ncc(Cl)cc1I
Reactant: C#CC
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC#Cc1cc(Cl)cnc1N
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
Propyne (35 g, 0.87 mol) was condensed into a pre-weighed flask cooled to ca. −40° C. containing THF (100 mL). The solution was added via cannula to a cooled (0-5° C.), degassed mixture of 5-chloro-3-iodo-pyridin-2-ylamine (81.4 g, 0.32 mol), bis(triphenylphosphine)dichloropalladium(0) (4.49 g, 6.4 mmol), copper (I) iodide (1.46 g, 7.67 mmol) and triethylamine (97.3 g, 134 mL, 0.98 mol) in THF (900 mL). The mixture was stirred at 0-5° C. for 30 minutes then for a further 30 minutes at ambient temperature. The solid was removed by filtration and the cake washed with THF. The filtrate was diluted with ethyl acetate and extracted with 2M hydrochloric acid (×3). The combined acid extract was washed with diethyl ether and then made basic by careful addition of potassium carbonate then extracted with diethyl ether (×3). The combined organic layer was dried (Na2SO4), filtered and evaporated to afford the title compound as a brown solid (53.8 g, quantitative yield). LCMS (Method B): RT=3.55 min, M+H+=167/169. 1H NMR (300 MHz, CDCl3): 7.92 (d, J=2.5 Hz, 1H), 7.42 (d, J=2.5 Hz, 1H), 5.00 (s, 2H), 2.10 (s, 3H).
Reaction SMILES: Cl[CH:2]1[C:6](=[O:7])[C:5]2[CH:8]=[C:9](C)[CH:10]=[CH:11][C:4]=2[S:3]1=[CH:13][C:14]([OH:16])=[O:15].[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=CC=1.[C:24](O)(=O)C>>[S:23]1[CH:17]=[CH:22][CH:21]=[C:20]1[CH:2]1[C:6](=[O:7])[C:5]2[C:8]([CH3:24])=[CH:9][CH:10]=[CH:11][C:4]=2[S:3]1=[CH:13][C:14]([OH:16])=[O:15]
Reactant: Sc1ccccc1
Reactant: CC(=O)O
Reactant: Cc1ccc2c(c1)C(=O)C(Cl)S2=CC(=O)O
Product: Cc1cccc2c1C(=O)C(c1cccs1)S2=CC(=O)O
Yield: 85.4 %

Procedure:
25.5 g (0.1 mole) of 2-chlorocarboxymethylene-5-methyl-[2H]-benzothiophen-3-one (obtained in accordance with German Offenlegungsschrift No. 2 804 842) are suspended at 20° C. in 300 ml of anhydrous acetic acid and to this suspension are added 11 g (0.1 mole) of thiophenol. The reaction mixture is then heated for 11/2 hours to 50° C. After cooling, the orange red precipitate is collected by filtration, washed with anhydrous acetic acid and dried at 60° C./13000 Pa, affording 28 g (85.4% of theory) of 2-thiophenyl-carboxymethylene-4-methylbenzothiophen-3-one in the form of orange red crystals with a melting point of 164°-167° C. (decompos.).