Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.[CH2:32]([O:35][CH3:36])[C:33]#[CH:34]>>[F:24][C:23]([F:26])([F:25])[C:22]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[C:2]([C:34]#[C:33][CH2:32][O:35][CH3:36])[CH:3]=1)([OH:31])[C:27]([F:30])([F:29])[F:28]
Reactant: C#CCOC
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Product: COCC#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(S(=O)(=O)c2cccs2)CC1

Procedure:
Following the procedure outlined for Example 152, 2-(3-Bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (Example 69) was coupled to methyl propargyl ether (Aldrich, St. Louis, Mo.) to afford 1,1,1,3,3,3-hexafluoro-2-(3-(3-methoxyprop-1-ynyl)-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)propan-2-ol. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.10 (dd, J=1.00, 4.90 Hz, 1H), 7.69 (dd, J=0.88, 3.62 Hz, 1H), 7.54-7.60 (m, 2H), 7.33 (dd, J=4.01, 4.79 Hz, 1H), 7.12 (d, J=8.80 Hz, 1H), 4.30 (s, 2H), 3.27-3.30 (m, J=5.10 Hz, 4H), 3.23 (s, 3H), 3.10 (d, J=4.30 Hz, 4H); m/z (ESI, +ve ion) 543.2 (M+H)+. GK-GKRP IC50 (Binding)=0.363 μM. GK-GKRP EC50 (LC MS/MS-2)=0.675 μM.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C([Li])CCC.[CH3:15][O:16][CH2:17]Cl.O>CCOCC.CCCCCC>[CH3:15][O:16][CH2:17][CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2c(c1)CCC2
Reactant: COCCl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: COCC1C=Cc2ccccc21
Reaction time: 0.25 h
Yield: 78 %

Procedure:
To a solution of indane (240 g) in dry ether (1 l) was slowly added, with stirring under a nitrogen atmosphere, 2.2 M solution (1 l) of n-butyllithium in n-hexane at -40° C over an hour. After 15 minutes, to this solution was added chloromethyl methyl ether (170 g) in dry ether (150 ml) under nitrogen at -55° C over 30 minutes. After stirring for another 30 minutes, water (1 l) was added with efficient stirring. The ether layer was separated, the aqueous phase extracted with ether (100 ml) twice, and the combined ether extract was washed with brine and dried over MgSO4. The ether was evaporated and the residual oily substance was distilled to give 1-methoxymethyl indene as yellow oil. (b.p. 50° C/0.2 mmHg, 258 g yield 78%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:3]=1.C[C:15]1[CH:16]=[C:17]([N:22]2CC[NH:25][CH2:24][CH2:23]2)[CH:18]=[CH:19][C:20]=1[CH3:21]>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:21][C:20]3[CH:19]=[C:18]4[C:17](=[CH:16][CH:15]=3)[NH:22][CH2:23][CH2:24][NH:25]4)[CH2:10][CH2:9]2)[CH:3]=1
Reactant: Cc1ccnc(N2CCNCC2)c1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Product: Cc1ccnc(N2CCN(Cc3ccc4c(c3)NCCN4)CC2)c1

Procedure:
Example 10 was prepared according to Example 2 except that in Step A 1-(4-methylpyridin-2-yl)piperazine is substituted for 1-(3,4-dimethylphenyl)piperazine; mp 179°-180° C.
Reaction SMILES: [Br:1][C:2]12[CH2:9][N:8](C(OCC)=O)[CH2:7][CH:6]1[N:5]([CH3:15])[CH2:4][CH2:3]2>Cl>[Br:1][C:2]12[CH2:9][NH:8][CH2:7][CH:6]1[N:5]([CH3:15])[CH2:4][CH2:3]2
Reactant: CCOC(=O)N1CC2N(C)CCC2(Br)C1
Agent: Cl
Product: CN1CCC2(Br)CNCC12

Procedure:
18.4 g (60.7 mmol, 91.4%) of ethyl 5-bromo-2-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are refluxed overnight together with 120 ml of concentrated hydrochloric acid. The mixture is concentrated, the concentrate is taken up in 50 ml of water, this mixture is rendered alkaline using potassium carbonate and extracted five times using 100 ml portions of chloroform. The extracts are dried over potassium carbonate, concentrated and distilled.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2([NH:10]C(=O)OC(C)(C)C)[CH2:9][CH2:8]2)=[N:3][CH:2]=1.[ClH:18]>O1CCOCC1>[ClH:18].[N:1]1[CH:6]=[CH:5][C:4]([C:7]2([NH2:10])[CH2:9][CH2:8]2)=[N:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccncn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1(c2ccncn2)CC1

Procedure:
A solution of tert-butyl 1-(pyrimidin-4-yl)cyclopropylcarbamate (0.100 g, 0.425 mmol, 1.0 eq), in 4.0 M HCl in 1,4-dioxane (4.0 ml) was stirred at r.t. for 5 hr. The reaction mixture was concentrated completely and the HCl salt was taken to next step.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)=[O:3].[CH3:14][C:15]([O:17]C(C)=O)=[O:16]>CCN(CC)CC>[F:13][C:10]([F:11])([F:12])[C:7]1[CH:8]=[CH:9][C:4]([C:2]([CH:1]=[CH:14][C:15]([OH:17])=[O:16])=[O:3])=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Product: O=C(O)C=CC(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 0.33 h

Procedure:
Freshly fused ZnCl2 (82 g, 0.6 mole) was dissolved in dry Et2O (400 ml) and added dropwise to the Grignard reagent prepared from 4-bromobenzotrifluoride (112.5g, 0.5 mole) and Mg (12.2 g, 0.5 g-atom) in Et2O (600 ml). Maleic anhydride (44 g, 0.45 mole) in Et2O (400 ml) was added over 30 minutes with stirring at reflux. After 2 hours, the mixture was cooled and acidified to pH 2 with 10% HCl. The Et2O layer was separated and dried (MgSO4), and the Et2O evaporated. The residue was recrystallized from C6H6 (x3) to yield the title compound, 24.5 g (21%), mp 149°-151°. Anal. (C11H7F3O3) C, H, F. An alternative procedure is as follows. A mixture of 4-trifluoromethylacetophenone (18.8 g) glyoxylic acid monohydrate (18.8 g), Ac2O(20 ml) and a drop of Et3N was heated to 135°, internal temperature. More Et3N (2 ml) was added, and the mixture was held at 135° for 20 minutes. The mixture was cooled and evaporated to dryness in vacuo. The solid residue was digested with H2O, filtered, dried and recrystallized from C6H6 to give the title compound, 12.2 g (50%), mp 149°-151°.
Reaction SMILES: O[C@@H:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:3]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH2:4][NH:5][CH3:6].Cl.C(N(S(F)(F)[F:30])CC)C.O>C(Cl)Cl>[F:30][C@H:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:3]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH2:4][NH:5][CH3:6]
Reactant: CCN(CC)S(F)(F)F
Reactant: CNC[C@H](c1ccc2ccccc2c1)[C@@H](O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CNC[C@H](c1ccc2ccccc2c1)[C@H](F)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of the (2S,3R)-3-hydroxy-N-methyl-2-(naphthalen-2-yl)-3-phenylpropan-1-amine.HCl (48.6 mg, 0.167 mmol) in 2 mL of DCM was added neat diethylaminosulfur trifluoride (0.073 mL, 0.67 mmol). The reaction mixture was stirred for 1 h at room temperature. Water (10 mL) was added very cautiously (exothermic reaction), and the aqueous reaction mixture was filtered through 0.45μ Teflon filters. The pure product was isolated by reverse phase HPLC (Vydac 2.2×25 cm, C-8, elution with a gradient of 10% B-100% B in 90 min, B=80% aq. CH3CN with 0.1% TFA, A=H2O with 0.1% TFA); FR=8 mL/min; λmax=254 nm; RT==48.5 min). Evaporation of the solvent from product containing HPLC fractions furnished the product as a gummy residue that turned into a white solid after conversion to a hydrochloride salt and drying under high vacuum. Yield 8.9 mg, 18.2%. MCJ001-F-SS: 1H NMR (CD3OD) δ 7.87-7.72 (m, 4H), 7.67 (s, 1H), 7.52-7.43 (m, 3H), 7.32-7.13 (m, 4H), 5.81 (dd, J=46.5, 8.5 Hz, 1H), 3.91-3.65 (m, 4H), 2.72 (s, 3H); MS (ESI): m/z 294.12 (M+1); [α]D20 c 0.03, 9:1 EtOH:H2O). MCJ001-C1-SS: 1H NMR (CD3OD) δ 7.85-7.69 (m, 4H), 7.66 (s, 1H), 7.49-7.41 (m, 3H), 7.33-7.04 (m, 4H), 5.38 (d, J=9.4 Hz, 1H), 4.07-3.-3.07 (m, 4H), 2.69 (s, 3H); MS: m/z 310.30 (M+1)+; [α]D20 c, +9.5 (c 0.335, 9:1 EtOH:H2O)
Reaction SMILES: [CH3:1][C:2]1[N:18]=[C:5]2[C:6](=[O:17])[CH2:7][CH:8]3[C:13]([CH:12]=[N:11][C:10]([CH3:15])([CH3:14])[C:9]3=[O:16])=[C:4]2[N:3]=1.Cl.[CH2:20]([N:22]([CH2:25][CH2:26][Cl:27])[CH2:23][CH3:24])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[ClH:27].[CH3:1][C:2]1[N:18]=[C:5]2[C:6](=[O:17])[CH:7]([CH2:21][CH2:20][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:8]3[C:13]([CH:12]=[N:11][C:10]([CH3:14])([CH3:15])[C:9]3=[O:16])=[C:4]2[N:3]=1
Reactant: CCN(CC)CCCl
Reactant: CC1=NC2=C3C=NC(C)(C)C(=O)C3CC(=O)C2=N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCC1C(=O)C2=NC(C)=NC2=C2C=NC(C)(C)C(=O)C21

Procedure:
4.2 gm of 2,7,7-trimethyl-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione were dissolved in 100 ml of dimethylformamide, and the solution was admixed with 3.4 gm of diethylamino ethyl chloride hydrochloride and 4.1 gm of potassium carbonate. The mixture was refluxed for 8 hours, the solvent was distilled off in vacuo, the residue was admixed with water and extracted with chloroform. The chloroform phase was evaporated and the residue was purified on a silicagel column (eluant: chloroform/acetone 19:1). The dihydrochloride was precipitated from acetone/methanol with ethereal hydrochloric acid and recrystallized from acetone/methanol.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH:40]=2)O1.[B].ClCCl.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C(OCC)(=O)C>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: O=C([O-])[O-]
Agent: [B]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC1Cc2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 120 °C
Yield: 97.5 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.313 g, 0.750 mmol, Example 49, Step 6), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.301 g, 0.975 mmol, Boron Molecular, Cat. No. BM550), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (38 mg, 0.045 mmol), potassium carbonate (415 mg, 3.00 mmol) in water (2.2 mL, 120 mmol) and 1,4-dioxane (4.5 mL) was degassed and recharged with nitrogen three times, and then heated at 120° C.) (oil bath temperature) for 2 h. After cooling, the mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in haxene (0-50%) to give the desired product (380 mg, 97.5%). LCMS (M+H)+: m/z=520.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH:23]=O)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:26]([NH2:28])[CH3:27]>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH2:23][NH:28][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc([N+](=O)[O-])cc2C=O)c1
Product: CCNCc1cc([N+](=O)[O-])ccc1-c1cc(CC(=O)OCC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 11, Step 4, using the following starting materials: (2′-formyl-6-methoxy-4′-nitro-biphenyl-3-yl)-acetic acid ethyl ester and ethylamine (2M in THF).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:16])[C:12]=2[F:15])[CH2:7]1)=[O:5])[CH3:2].[CH3:28][C:29]([CH3:40])=[CH:30]B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].N#N>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4]([C:6]1([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=2[CH:28]=[C:29]([CH3:40])[CH3:30])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:16])[C:12]=2[F:15])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)=CB1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccc(F)c(F)c2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1COCCO1
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=C(C)C)Cc2ccc(F)c(F)c2C1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a solution of 6-(4,5-difluoro-2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (386) (2.55 g, 5.25 mmol) and 2-methyl-1-propenyl boronic acid pinacol ester (364 mg, 10.5 mmol) in dioxane (100 mL) is added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (350 mg, 8.2% mmol) and 2M aqueous solution of K2CO3 (7.87 mL, 15.75 mmol). The resulting reaction mixture is filled in with N2, heated to 100° C. and stirred continuously for 6 h. Reaction mixture is filtered and concentrated in vacuo, and the resulting residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0%-50% EtOAc in heptane) to give a pure product (387) as light brown solid (1.24 g, 57%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C@@H:3]2[CH2:7][N:8]([C:10]3[N:15]=[C:14]([NH:16][C:17]4[CH:21]=[CH:20][NH:19][N:18]=4)[CH:13]=[C:12]([CH3:22])[N:11]=3)[CH2:9][C@@H:2]12.[C:23](=O)([O:34][C@@H:35]([CH3:40])[C:36]([F:39])([F:38])[F:37])[O:24]C1C=CC([N+]([O-])=O)=CC=1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH3:22][C:12]1[CH:13]=[C:14]([NH:16][C:17]2[CH:21]=[CH:20][NH:19][N:18]=2)[N:15]=[C:10]([N:8]2[CH2:7][C@@H:3]3[C@H:2]([O:1][CH2:6][CH2:5][N:4]3[C:23]([O:34][C@@H:35]([CH3:40])[C:36]([F:39])([F:38])[F:37])=[O:24])[CH2:9]2)[N:11]=1
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: Cc1cc(Nc2cc[nH]n2)nc(N2C[C@H]3NCCO[C@@H]3C2)n1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc[nH]n2)nc(N2C[C@@H]3[C@@H](C2)OCCN3C(=O)O[C@@H](C)C(F)(F)F)n1
Temperature: 100 °C

Procedure:
To a mixture of 2-[(4aR,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl]-6-methyl-N-(1H-pyrazol-3-yl)pyrimidin-4-amine (20 mg) in CHCl3 (3 mL) were added 4-nitrophenyl (2S)-1,1,1-trifluoropropan-2-yl carbonate (37 mg) prepared in Referential Example 2 and DIEA (30 mg) at room temperature. After 4-hour stirring at 100° C. in a sealed tube, the resulting mixture was cooled to room temperature and concentrated. The residue was diluted with MeOH (5 mL). To the resulting mixture was added potassium carbonate (100 mg) at 0° C. and stirred at 0° C. for 30 min. The mixture was poured into saturated aqueous solution of NH4Cl and extracted with CHCl3. The extract was washed with brine, dried over MgSO4 and concentrated. The residue was purified with silica gel column chromatography (eluent: CHCl3/MeOH=99/1˜80/20) to give (2S)-1,1,1-trifluoropropan-2-yl (4aR,7aR)-6-[4-methyl-6-(1H-pyrazol-3-ylamino)pyrimidin-2-yl]hexahydropyrrolo[3,4-b][1,4]oxazine-4(4aH)-carboxylate as a pale yellow foam.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19](Br)=[N:18][C:17]=3[N:16]([CH3:29])[C:14]2=[O:15])[N:3]=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.O.[Cl-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[N:18][C:17]=3[N:16]([CH3:29])[C:14]2=[O:15])[N:3]=1
Reactant: C1CNCCN1
Reactant: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCNCC2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 200 °C

Procedure:
A mixture of 300 mg of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine and 290 mg of piperazine in 5 ml of N,N-dimethylformamide is heated at 200° C. for 5 min in a microwave oven. After cooling to room temperature, the reaction mixture is treated with water and saturated sodium chloride solution and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The solid flask residue is triturated with diethyl ether, filtered off with suction and dried at 45° C. in a circulating air drying oven.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=O)[C:5]2[S:10][CH2:9][CH2:8][N:7]([CH3:11])[C:6]=2[CH:12]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:30][CH:31]1[CH:36]2[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]2)[CH2:32]1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:30][CH:31]2[CH:36]3[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]3)[CH2:32]2)=[O:15])[C:5]2[S:10][CH2:9][CH2:8][N:7]([CH3:11])[C:6]=2[CH:12]=1
Reactant: NC1CN2CCC1CC2
Reactant: CN1CCSc2c(C(=O)O)cc(Cl)cc21
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN1CCSc2c(C(=O)NC3CN4CCC3CC4)cc(Cl)cc21

Procedure:
To a solution of 1.8 g of 6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzothiazine-8-carboxylic acid in 30 ml of ethyl acetate was added 1.05 g of triethylamine, and then added 0.891 g of pivaloyl chloride dropwise with stirring at -10° C. to -5° C. followed by stirring the mixture at the same temperature for 30 minutes. To the resultant mixture was added a solution of 1.12 g of 3-aminoquinuclidine in 15 ml of ethyl acetate at -10° to -5° C. and then stirred at room temperature for an hour. After the reaction solution was washed with water, dried over anhydrous sodium sulfate and concentrated, the crystalline residue thus obtained was recrystallized from ethyl acetate to give 6-chloro-4-methyl-N-(3-quinuclidinyl)-3,4-dihydro-2H-1,4-benzothiazine-8-carboxamide as yellow crystals. Melting point: 195°-196° C.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][O:32][Si](C(C)(C)C)(C)C)[C:20]([CH3:40])=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C@H:21]([CH2:31][OH:32])[C:20]([CH3:40])=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@@H]1C=C(C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCON([C@@H]1C=C(C)[C@@H](CO)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 79.3 %

Procedure:
(2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-((tert-butyldimethylsilyloxy)methyl)-3-methyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 80, 7.05 g, 11.79 mmol) in THF (100 mL) was charged with nitrogen and cooled in an ice-bath. Tetrabutylammonium fluoride in THF (14.15 mL, 14.15 mmol) was added to the solution and stirred at rt. The reaction mixture was evaporated and the crude product was loaded onto silica and purified via flash chromatography (30-100% EA/Hexanes, 40 g column), to obtain the desired product (4.52 g, 79%) as a pale yellow foam.
Reaction SMILES: Cl[C:2]([N:4]([C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[N:14]=1)[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[Cl:12])=[O:3].[NH3:21]>C(Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=1[N:4]([C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[N:14]=1)[C:2]([NH2:21])=[O:3]
Reactant: N
Reactant: Cc1cc(C)nc(N(C(=O)Cl)c2cc(Cl)ccc2Cl)n1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)nc(N(C(N)=O)c2cc(Cl)ccc2Cl)n1

Procedure:
4.0 g (0.012 mole) of N-chlorocarbonyl-N-(4,6-dimethylpyrimidin-2-yl)-2,5-dichloroaniline are dissolved in 50 ml of chloroform. An excess of ammonia gas is introduced into the solution. When the exothermic reaction has subsided, the reaction mixture is washed twice with water, dried with magnesium sulfate and concentrated by evaporation.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:36])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[CH2:1]([N:8]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][N+:13]([O-:36])=[CH:12][C:11]=1[F:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OCCN(Cc1ccccc1)C(=O)c1ccncc1F
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCN(Cc1ccccc1)C(=O)c1cc[n+]([O-])cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a solution of the compound (26.2 g) obtained in step 1 in THF (135 mL) was added 70% m-chloroperbenzoic acid (m-CPBA) (16.2 g) at 0° C., and the mixture was stirred at room temperature for 4 hr. m-CPBA (16.2 g) was further added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into aqueous sodium thiosulfate solution, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 10→80% ethyl acetate/hexane) to give N-benzyl-N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-fluoroisonicotinamide 1-oxide (19.0 g, 70%) as a pale-yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][C:25]1[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1)[NH2:20].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[NH:10][C:3]2[C:2]([NH:20][C:19]3[CH:21]=[CH:22][C:23]([O:24][C:25]4[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=4)=[C:17]([CH3:16])[CH:18]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=1
Reactant: Clc1ncnc2cc(-c3ccco3)[nH]c12
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cc(-c5ccco5)[nH]c34)cc2C)cn1
Temperature: 140 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
A mixture of 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (110 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (161 mg) and 1-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140° C. for 2 hrs, poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (25 mL×2) and the organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→0:1). The object fraction was concentrated under reduced pressure. Chloroform-diisopropyl ether was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60° C. to give the title compound (114 mg).