Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>O1CCOCC1>[F:22][C:2]([F:21])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[C:13]4[N:12]([C:23](=[O:24])[NH:20][C:18](=[O:19])[C:17]=4[CH:16]=[N:15]3)[CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: NC(=O)c1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n2c3c1cnn3C(c1cccc(C(F)(F)F)c1)=CC2
Yield: 59.9 %

Procedure:
To a stirred mixture of 10.0 g of 4,5-dihydro-7-(3-(trifluoromethyl)phenyl)pyrazolo(1,5-a)pyrimidine-3-carboxamide (prepared as described in Example 8) in 200 ml of dioxane at room temperature under nitrogen is added 20.0 g of 1,1'-carbonyldiimidazole. The mixture is then heated at reflux for 5 hours, and then is cooled and filtered. The filtrate is evaporated to dryness in vacuo and an excess of water is added to the residue. The white solid which forms is collected and is recrystallized from acetonitrile-ethanol to give 6.5 g of the desired product as a white solid, mp 260-262° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=O)=[CH:12][CH:11]=1.[OH-].[NH4+].[OH-].[Na+]>>[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]2[NH:1][C:2]3=[N:3][CH:4]=[CH:5][CH:6]=[C:7]3[N:8]=2)=[CH:12][CH:11]=1
Reactant: Nc1cccnc1N
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc(-c2nc3cccnc3[nH]2)cc1
Temperature: 180 °C
Yield: 4.4 %

Procedure:
A mixture of 2,3-diaminopyridine (10.9 g, 0.1 mole), p-chlorobenzoic acid (16.0 g, 0.102 mole), and 150 g of polyphosphoric acid was heated at 180° C. in an oil bath for 31/2 hr. The reaction mixture was neutralized with concentrated ammonium hydroxide and basified with sodium hydroxide. The precipitate was filtered and washed with water. The solid was treated with dilute sodium hydroxide, filtered, washed with water, and dried under high vacuum at 60° C. overnight. A 3-g sample was dissolved in hot methanol, and the solution was treated with 3 g of charcoal, and filtered through a Celite pad. The product crystallized from the filtrate upon cooling. The precipitate was filtered, washed with methanol-water (2:1), and dried under high vacuum at 70° C. to give 1.0 g of the title compound, mp 305°-8° C. with sublimation.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][NH:6][C:7](=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:2].CN1C=CN=C1.[C:33](Cl)(=[O:49])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48].C(N(CCCC)CCCC)CCC>[Ti](Cl)(Cl)(Cl)Cl.O.ClC1C=CC=CC=1>[C:7]([NH:6][CH:5]([C:33](=[O:49])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:4]([O:3][CH2:1][CH3:2])=[O:26])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCC(=O)NCC(=O)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cn1ccnc1
Solvent: CCCCN(CCCC)CCCC
Solvent: Clc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)NC(C(=O)CCCCCCCCCCCCCCC)C(=O)OCC
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 76.6 %

Procedure:
A chlorobenzene solution (33.0 ml) of N-octadecanoylglycine ethyl ester (2.00 g, 5.41 mmol) and N-methylimidazole (533 mg, 6.49 mmol) was cooled to −10° C., and palmitoyl chloride (1.49 g, 5.41 mmol) was added thereto in nitrogen atmosphere. After the mixture was stirred for 45 minutes at the same temperature, titanium tetrachloride (3.60 g, 18.94 mmol) and tributylamine (4.01 g, 21.64 mmol) were added thereto. The resulting mixture was stirred for 1.5 hours at −10° C. After water (25 ml) was added thereto and the mixture was heated to room temperature, the organic layer was separated. It was confirmed by comparative analysis with sample product using HPLC that the organic layer contained 2.52 g of the title compound (yield: 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=O)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:22])[CH:4]=1.Cl.Cl.[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]2([OH:38])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:27][CH:26]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:38][C:32]1([CH2:31][C:28]2[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=2)[CH2:37][CH2:36][N:35]([C:19](=[O:21])[CH2:18][O:17][CH2:16][CH2:15][N:13]([CH3:14])[S:10]([C:6]2[C:5]([CH3:22])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=2[CH3:9])(=[O:11])=[O:12])[CH2:34][CH2:33]1
Reactant: OC1(Cc2ccncc2)CCNCC1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)O)c(C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)N2CCC(O)(Cc3ccncc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (77 mg, 0.475 mmol) was added to a solution of 2-(2-(4-methoxy-N,2,6-trimethylphenylsulfonamido)-ethoxy)acetic acid (acid unit S2) (150 mg, 0.453 mmol) in methylene chloride (7 ml), and the mixture was stirred for 1 h at room temperature. A solution of 4-(pyridin-4-ylmethyl)piperidin-4-ol dihydrochloride (120 mg, 0.453 mmol) dissolved in methylene chloride (3 ml) and triethylamine (0.18 ml) was then added, and the reaction mixture was stirred overnight at room temperature. Saturated sodium bicarbonate solution (10 ml) was then added to the reaction mixture, and the aqueous phase was then extracted with methylene chloride (20 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried with sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography with ethyl acetate/methanol (10:1). Yield: 130 mg (57%).
Reaction SMILES: [Se](=O)=[O:2].[Br:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH:16]3[CH2:21][CH2:20][CH:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17]3)[CH:13]=2)[N:8]=[C:7]([CH3:26])[CH:6]=1>O1CCOCC1>[Br:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:18][CH2:17]3)[CH:13]=2)[N:8]=[C:7]([CH:26]=[O:2])[CH:6]=1
Reactant: O=[Se]=O
Reactant: Cc1cc(Br)c2cc(OC3CCC(C(C)(C)C)CC3)ccc2n1
Solvent: C1COCCO1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(C=O)cc(Br)c3c2)CC1
Temperature: 50 °C
Reaction time: 96 h

Procedure:
To a suspension of Selenium dioxide (0.333 g, 3.00 mmol) in 1,4-Dioxane (8.0 mL) was added a solution of 4-Bromo-6-(4-tert-butyl-cyclohexyloxy)-2-methyl-quinoline (0.469 g, 1.25 mmol) in 1,4-Dioxane (4.0 mL). The mixture was sealed and was heated at 50° C. in an oil bath. After 4 d, the reaction was filtered through Celite and washed with dioxane. The solvent was evaporated and the residue was purified on silica gel column using 0-25% ethyl acetate in hexanes as eluent. Isolated was the product (Rf=0.68 in 3:1 hexanes/ethyl acetate) in 362 mg yield, 74%. ESI (M+H+): 390.10/392.10.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Li+].[Cl-].[CH3:25][O:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][O:39][CH3:40])[CH:32]=[CH2:33]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[CH3:25][O:26][CH2:27][O:28][C:29]1[CH:30]=[C:31](/[CH:32]=[CH:33]/[C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH2:38][O:39][CH3:40]
Reactant: C=Cc1ccc(OCOC)c(OCOC)c1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCOc1ccc(/C=C/c2ccc(S(=O)(=O)N3CCOCC3)cc2)cc1OCOC
Temperature: 85 °C
Yield: 83.1 %

Procedure:
N-(4 -bromobenzenesulfonyl)morpholine (1.0 g, 3.266 mmol) was mixed with (n-Bu)4NBr (TBAB, 1.05 g, 3.266 mmol), K2CO3 (0.451 g, 3.266 mmol) and LiCl (0.1384 g, 3.266 mmol under argon atmosphere. Then dry DMF (25 mL) and 3,4-di(methoxymethoxy)styrene (0.7324 g, 3.226 mmol) were added, followed by the catalyst Pd(OAc)2 (73 mg, 0.3266 mmol). The mixture was heated between 80-90° C. under argon atmosphere for 24 hours. After removal of the DMF solvent, the residue obtained was loaded to a silica gel column with CH2Cl2 as solvent. The column was eluted with CH2Cl2/EtOAc (2:1, v/v) to yield 1.205 g of N-{4-[2-(3,4-di(methoxymethoxy)phenyl)-trans-vinyl]benzenesulfonyl}morpholine as a yellowish solid (2.6805 mmol, yield 82.1%). 1H NMR (CDCl3, 300.16 MHz) δ (ppm) 7.72 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H), 7.38 (d, J=1.7 Hz, 1H), 7.20-7.13 (m, 3H), 7.00 (d, J=16.2 Hz, 1H), 5.30 (s, 2H), 5.27 (s, 2H), 3.77-3.74 (m, 4H), 3.56 (s, 3H), 3.53 (s, 3H) and 3.04-3.01 (m, 4H). MS (ESI) m/z: 450 (M+1)+ and 472 (M+23)+.
Reaction SMILES: C(O)(=O)C.OO.[Cl:7][C:8]1[CH:9]=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]([CH3:19])=[C:12]2[C:17]=1S[CH2:15][CH2:14][C:13]2=[O:18].[S:25]([O-:28])(O)=[O:26].[Na+]>O>[Cl:7][C:8]1[CH:9]=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]([CH3:19])=[C:12]2[C:17]=1[S:25](=[O:28])(=[O:26])[CH2:15][CH2:14][C:13]2=[O:18]
Reactant: O=S([O-])O
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C(=O)CCS2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(Cl)c2c(c1C)C(=O)CCS2(=O)=O
Yield: 54 %

Procedure:
3 Milliliters of acetic acid and 1.75 g (15.47 mmol) of a 30 wt % hydrogen peroxide aqueous solution were added to 2.00 g (7.03 mmol) of 8-chloro-6-ethoxycarbonyl-5-methylthiochroman-4-one in a 50-ml round-bottomed flask, and the mixture was allowed to react at 70° C. for 2 hours. The reaction mixture was diluted with about 50 ml of water, and a sodium hydrogensulfite was added to decompose excess hydrogen peroxide. Then, the mixture was extracted with ethyl acetate. An organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution and with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to give 1.20 g (yield 54%) of 8-chloro-6-ethoxycarbonyl-5-methylthiochroman-4-one-1,1-dioxide.
Reaction SMILES: [Cl-].[Li+].C(OP([CH:11]([CH2:17][CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.C1CCN2C(=NCCC2)CC1.[C:38]1([CH:48]=O)[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1.Cl>C1COCC1>[C:38]1([CH:48]=[C:11]([CH2:17][CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: CCOC(=O)C(CCCOC1CCCCO1)P(=O)(OCC)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)C(=Cc1cccc2ccccc12)CCCOC1CCCCO1
Yield: 84 %

Procedure:
579 mg of lithium chloride was suspended in 20 ml of dry THF under an argon stream, and 5.0 g of ethyl 2-diethylphosphono-5-(2-tetrahydropyranyloxy)pentanoate was added under stirring. After stirring the mixture for 5 minutes at room temperature, 2.6 g of DBU was added, and the mixture was stirred at room temperature for 10 minutes. Then, 1.7 g of α-naphthoaldehyde was added, and the mixture was stirred at room temperature overnight. Then, the reaction solution was neutralized with 1N hydrochloric acid under cooling with ice and extracted with ethyl acetate. The ethyl acetate layer thereby obtained was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1) to obtain 3.37 g of ethyl 3-(1-naphthyl)-2-[3-(2-tetrahydropyranyloxy)propyl]-2-propenoate as slightly yellow oily substance.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[Br:17]N1C(=O)CCC1=O.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].OS([O-])=O.[Na+]>C1COCC1.C(OCC)(=O)C>[Br:17][C:8]1[CH:7]=[CH:6][C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][C:3]=1[CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cccc(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.7 %

Procedure:
To a solution of 1-ethyl-3-(phenylmethoxy)-benzene (15 g, 71 mmol) in THF (200 ml) were added N-bromosuccinimide (16.3 g, 92 mmol) and concentrated sulfuric acid (2.4 ml). The solution was stirred for 5 h at ambient temperature. Sodium bicarbonate (3.6 g) and 10% aqueous NaHSO3 solution (400 ml) were added under ice cooling. The resulting mixture was stirred for 10 min and then poured into ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined extracts were washed with ice water and brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a yellow oil which was purified by column chromatography (silica gel, cyclohexane) to yield 17.1 g (58.7 mmol, 83%) of the title compound as colorless liquid.
Reaction SMILES: [NH:1]([C:3](=[O:18])[CH2:4][C:5]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:6]=1[C:7](O)=[O:8])[NH2:2]>CC(O)=O>[CH3:15][O:14][C:12]1[C:11]([O:16][CH3:17])=[CH:10][C:6]2[C:7](=[O:8])[NH:2][NH:1][C:3](=[O:18])[CH2:4][C:5]=2[CH:13]=1
Reactant: COc1cc(CC(=O)NN)c(C(=O)O)cc1OC
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)C(=O)NNC(=O)C2
Reaction time: 0.08 h

Procedure:
To 15 ml of AcOH at 100° C., add 1.5 g (5.9 mmol) of 2-(2-hydrazino-2-oxoethyl)-4,5-dimethoxy benzoic acid XI. After 5 minutes at 100° C., cool in an ice bath. Filter and wash twice with 1 ml of AcOH, twice with 2 ml of H2O, twice with 10 ml of Et2O.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[OH-].[K+].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1>C1(C)C=CC=CC=1.O.C(Cl)Cl>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CCc1nc(O)c(Cc2ccc3ccccc3c2)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (125 mg, 536 μmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.30 mL, 0.60 mmol) at RT followed by 2-(bromomethyl)naphthalene (123 mg, 556 μmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before extraction with CH2Cl2 (80 mL). The organic phase was isolated and washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) gave 41 mg of 1-ethyl-6,7-dimethoxy-4-(naphthalen-2-ylmethyl)isoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.42 M HCl solution in MeOH (4.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 1-ethyl-6,7-dimethoxy-4-(naphthalen-2-ylmethyl)isoquinolin-3-ol hydrochloride 19 as a yellow solid (44 mg, 20% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:29][C:30]([O:32][CH2:33][C@@H:34]2[CH2:39][O:38][CH2:37][CH2:36][N:35]2C(OC(C)(C)C)=O)=[O:31])=[CH:5][N:6]2[C:11]=1[C:10]([NH:12][C:13]1[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[N:17]=[CH:16]3)=[N:9][CH:8]=[N:7]2)[CH3:2].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH2:1]([C:3]1[C:4]([NH:29][C:30](=[O:31])[O:32][CH2:33][C@@H:34]2[CH2:39][O:38][CH2:37][CH2:36][NH:35]2)=[CH:5][N:6]2[C:11]=1[C:10]([NH:12][C:13]1[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[N:17]=[CH:16]3)=[N:9][CH:8]=[N:7]2)[CH3:2]
Reactant: CCc1c(NC(=O)OC[C@@H]2COCCN2C(=O)OC(C)(C)C)cn2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(NC(=O)OC[C@@H]2COCCN2)cn2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c12
Reaction time: 18 h
Yield: 97.1 %

Procedure:
3-[[[[[5-ethyl-4-[[1-(phenylmethyl)-1H-indazol-5-yl]amino]pyrrolo[2,1-f][1,2,4]triazin-6-yl]amino]carbonyl]oxy]methyl]-4-morpholinecarboxylic acid, (3S)-1,1-dimethylethyl ester (14.0 g, 22.3 mmol) was dissolved in methylene chloride (250 mL) and treated with trifluoroacetic acid (40 mL). The resulting solution was stirred for 18 h, then neutralized by the addition of saturated aqueous sodium carbonate. The organic phase was separated and dried over magnesium sulfate. Filtration and concentration of the filtrate gave 11.4 g of [5-ethyl-4-[[(1-phenylmethyl)-1H-indazol-5-yl]amino]pyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamic acid, (3S)-3-morpholinylmethyl ester as a yellow oil. This material was re-dissolved in methylene chloride (100 mL) and treated with 1M hydrochloric acid in ether (21.7 mL, 21.7 mmol). The solution was stirred for 30 min then concentrated under reduced pressure. Drying of the residue under high vacuum (0.5 mmHg) overnight afforded 11.6 g (92%) of [5-ethyl-4-[[(1-phenylmethyl)-1H-indazol-5-yl]amino]pyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamic acid, (3S)-3-morpholinylmethyl ester hydrochloride as an off-white solid.
Reaction SMILES: I[C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.O=O.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(N(CC)CC)C.CN(C=O)C.[Cu]I>[CH3:12][Si:13]([C:16]#[C:17][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1)([CH3:15])[CH3:14]
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: O=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1c[nH]c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 5-iodouracil (8 g, 30 mmol) in redistilled triethylamine (500 mL) and dry DMF (10 mL) was degassed with oxygen-free nitrogen for 15 minutes. Bis(triphenylophosphine)palladium (II) chloride (0.5 g), copper (I) iodide (0.5 g) and trimethylsilylacetylene (10 g, 102 mmol) were then added and the mixture was heated with stirring at 50° C. for 24 hours. The cooled reaction mixture was filtered, the filtrate evaporated to dryness and the residue dissolved in dichloromethane (500 mL). The organic solution was washed with a 2% aqueous solution of disodium EDTA (3×250 mL), water (3×200 mL), dried (Na2SO4) and evaporated to dryness. The residue was triturated with ethanol to give the first crop of the title compound. The solid filtered from the reaction mixture was also found to contain the required product but in a more impure form and so was worked up as above in a separate batch to give a second crop.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[CH2:4][C:3]=1[C:14]([O:16]C)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[CH2:4][C:3]=1[C:14]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)C1
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccccc1)C1=C(O)c2ccccc2S(=O)(=O)C1

Procedure:
Preparation by Aminolysis of the β-Ketoester. -- A mixture of 11.7 g. (0.05 mole) of methyl 4-hydroxy-2H-1-benzothiopyran-3-carboxylate 1,1-dioxide, 7.0 g. (0.075 mole) of aniline, and 250 ml. of xylene was refluxed for 16 hr. in a Soxhlet apparatus, the thimble of which contained 20 g. of Linde type 4A molecular sieve. The mixture was cooled and the resulting precipitate was collected to give 12.8 g. (81%) of product, m.p. 204°-208° dec. Recrystallization from ethyl acetate gave 11.4 g. material, m.p. 205°-208° dec.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:25][CH2:24][C:21]2([CH2:23][CH2:22]2)[CH:20]([OH:26])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.COC(C)(C)C>[C:11]([O:15][C:16]([N:18]1[CH2:25][CH2:24][C:21]2([CH2:23][CH2:22]2)[C:20](=[O:26])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)C(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CC2)C(=O)C1
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
To a solution of oxalyl chloride (42.35 ml, 0.480 mol) in dichloromethane (910 ml) was added a solution of dimethylsulfoxide (68.24 ml, 0.961 mol) in dichloromethane (910 ml) at −70° C. within 45 min. The solution was stirred for 15 min and a solution of 4-hydroxy-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (91.00 g, 0.400 mol) in dichloromethane (910 ml) was added within 40 min keeping the internal temperature at below −60°. The mixture was stirred for 35 min and triethylamine (280.4 ml, 2.00 mol) was added at below −60° C. within 10 min. The cooling bath was removed and the yellow suspension was stirred for 1 h then quenched with water (1.4 l). The organic phase was separated, washed with water (3×1 l) and sat. aq. sodium chloride solution (3 l) and evaporated. The residual orange powder was dissolved in tert-butyl methyl ether (1.40 l), the turbid solution filtered (Hyflo Speedex) to remove some insoluble material and the clear filtrate evaporated to provide crude 4-oxo-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester as yellow powder (91.9 g). The material was re-dissolved in tert-butyl methyl ether (300 ml) and purified by filtration over silica gel (700 g) using a 3:1 heptane/tert-butyl methyl ether mixture (6.5 l). Evaporation and drying (10 mbar, 40° C.) afforded 4-oxo-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester as whitish powder (80.58 g, 89%), GC purity 100a %.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17]([Cl:26])=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:33][Si:34]([CH2:37][CH2:38][O:39][CH2:40]Cl)([CH3:36])[CH3:35].O>CN(C=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[N:21]([CH2:40][O:39][CH2:38][CH2:37][Si:34]([CH3:36])([CH3:35])[CH3:33])[C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17]([Cl:26])=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(Cl)nc2nc(-c3cnn(Cc4ccccc4)c3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 0 °C
Reaction time: 20 h
Yield: 24.6 %

Procedure:
A mixture of 8-(1-benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.9 g, 2.44 mmol), K2CO3 (1.01 g, 7.32 mmol) in DMF (10 ml) were cooled to 0° C. and added SEM-Cl (1.3 ml, 7.32 mmol). The reaction mixture was stirred at 25° C. for 20 hours. To this reaction mixture water (100 ml) was added and extracted with ethyl acetate (3×30 ml). The combined organic layer was washed with brine (30 ml) and dried over Na2SO4. The organic layer was evaporated to dryness and the crude product was purified by column chromatography using silica gel (100-200 mesh) and 10-15% ethyl acetate in hexane as an eluent to obtain 8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.3 g, 25%) as a off white solid.