Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:11]3[S:12][CH:13]=[CH:14][C:10]=3[CH2:9][CH2:8][O:7]2)[CH2:3][CH2:2]1.C(=O)(OC(C)(C)C)[O:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O.[Cl-].[Na+]>CC1CCCO1>[N:1]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])[CH2:2][CH2:3][C:4]2([C:11]3[S:12][CH:13]=[CH:14][C:10]=3[CH2:9][CH2:8][O:7]2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: c1cc2c(s1)C1(CCNCC1)OCC2
Agent: [Cl-]
Agent: [Na+]
Solvent: CC1CCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)OCCc1ccsc12
Reaction time: 12 h
Yield: 99 %

Procedure:
Spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine] (60 g, 286.6 mmol) in 2-methyltetrahydrofuran (600 mL) is stirred at 22° C. for 10 min. Then, tert-butoxycarbonyl tert-butyl carbonate (65.6 g, 301 mmol) in 2-methyltetrahydrofuran (300 mL) is added dropwise. After 12 hr., an aqueous solution of sodium chloride (250 mL) is added and the organic layer is separated. The aqueous layer is washed twice with 2-methyltetrahydrofuran (2×50 mL) and the organic layers are combined and washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound in 99% yield. MS (m/z): 310 (M+1).
Reaction SMILES: [CH:1]([N:4]([CH2:16][CH2:17][CH2:18][CH:19]=O)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:30]([O:31][CH3:32])=[C:27]([O:28][CH3:29])[CH:26]=1>C(O)C.O=[Pt]=O>[Cl:15][C:10]1[CH:9]=[C:8]([S:5]([N:4]([CH2:16][CH2:17][CH2:18][CH2:19][N:22]([CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:30]([O:31][CH3:32])=[C:27]([O:28][CH3:29])[CH:26]=2)[CH3:21])[CH:1]([CH3:2])[CH3:3])(=[O:6])=[O:7])[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: CC(C)N(CCCC=O)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: CNCCc1ccc(OC)c(OC)c1
Agent: O=[Pt]=O
Solvent: CCO
Product: COc1ccc(CCN(C)CCCCN(C(C)C)S(=O)(=O)c2ccc(Cl)c(Cl)c2)cc1OC
Reaction time: 7 h

Procedure:
The aldehyde prepared in the preceding paragraph (8.90 g, 0.027 m) and N-methyl-homoveratrylamine (5.29 g, 0.027 m) in absolute ethanol (100 ml) containing PtO2 (0.6 g) was shaken under hydrogen (7 hours) and the reaction filtered and stripped to provide the crude product (13.32 g) as a dark greenish gum. This material was chromatographed, after removal of a small amount of insoluble solid, on dry column silica gel (500 g) with 30% methanol/70% ethyl acetate to provide the title compound (7.26 g) as a clear white gum.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.[NH:18]1[CH:22]=[C:21]([C:23]([OH:27])([C:25]#[CH:26])[CH3:24])[CH:20]=[N:19]1>>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:26]#[C:25][C:23]([C:21]4[CH:22]=[N:18][NH:19][CH:20]=4)([OH:27])[CH3:24])[CH:10]=3)[CH:6]=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: Nc1nccc(-n2ncc3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1cn[nH]c1
Product: CC(O)(C#Cc1ccc2cnn(-c3ccnc(N)n3)c2c1)c1cn[nH]c1
Reaction time: 1 h

Procedure:
The title compound was prepared by the procedure described in Example 2 (Step 2-b) by reacting 4-(6-bromo-1H-indazol-1-yl)pyrimidin-2-amine with 2-(1H-pyrazol-4-yl)but-3-yn-2-ol. The reaction was carried out at 75° C. for 1 hr: 1H NMR (500 MHz, DMSO) delta 1.81 (3H, s), 5.95 (1 H, br. s.), 6.93-7.17 (3H, m), 7.38 (1H, d, J=9.30 Hz), 7.70 (2H, br. s.), 7.88 (1H, d, J=8.35 Hz), 8.31 (1H, d, J=5.52 Hz), 8.49 (1H, s), 8.91 (1H, s), 12.71 (1H, br. s.); LC-MS: m/z=+346.50 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@@H:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]2)=[N:4][CH:5]=[C:6]([C:7](=[O:8])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:21]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCNC1
Product: CC(C)(C)OC(=O)NC[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 93.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and (R)-tert-butyl (pyrrolidin-3-ylmethyl)carbamate. LC-MS (Condition 6) tR=1.46 min, m/z=558.9 [M+H]+, m/z=581.0 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C>C1COCC1>[C:13]1([S:19]([N:8]2[C:9]3=[N:10][C:2]([Cl:1])=[CH:3][CH:4]=[C:5]3[CH:6]=[CH:7]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1ccc2cc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2ccc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
6-Chloro-7-azaindole (9.3 g, 61.1 mmol), prepared as described (Synthesis, 1992), was dissolved in 100 ml anhydrous THF under N2. At 0° C., a 60% dispersion of NaH 3.5 g (65.9 mmol) in mineral oil was added. After stirring for 1 hour at room temperature, the mixture was cooled (0° C.) and 8.7 ml (67.2 mmol) benzenesulfonyl chloride dissolved in 20 ml anhydrous THF was added. The reaction mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the mixture and the organic layer was washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether/PE gradient (1:4 to pure diethyl ether) to give 1-benzenesulfonyl-6-chloro-1H-pyrrolo[2,3-b]pyridine (amorphous, 14.4 g, 80.7%) (TLC diethyl ether/PE (1/1) Rf 0.37). LCMS; Rt: 1.98 min, ([M+H]+=293).
Reaction SMILES: [CH:1]1([CH2:7][C:8](Cl)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2([CH:23]([NH2:25])[CH3:24])[CH2:22][CH2:21][CH2:20]2)[CH:15]=[CH:16][C:17]=1[Cl:18].C(N(CC)CC)C>CCOCC>[CH:1]1([CH2:7][CH2:8][NH:25][CH:23]([C:19]2([C:14]3[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=3)[CH2:20][CH2:21][CH2:22]2)[CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(N)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: O=C(Cl)CC1CCCCC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(NCCC1CCCCC1)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reaction time: 3 h

Procedure:
Cyclohexylacetyl chloride (3.21 g) in dry ether (100 ml) was added over 30 minutes to a stirred mixture of 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine (4.88 g), triethylamine (2.5 g) and dry ether (100 ml) at 0°-6° C. After stirring for a further 3 hours the mixture was filtered and the residue was washed with dry ether. The filtrate and washings were combined, dried and evaporated. The residue was dissolved in tetrahydrofuran (50 ml) and the solution heated under reflux in an atmosphere of nitrogen. Borane-methyl sulphide complex (3 ml) was added from a syringe. The resulting mixture was heated under reflux for 12 hours after which it was cooled and ice-water and then 5N hydrochloric acid were added. The organic solvent was removed by evaporation and the residue was cooled, basified with 5N sodium hydroxide solution and extracted with ether. The extracts were washed with water, dried and the ether removed by evaporation. From the residue N-(2-cyclohexylethyl)-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine was obtained by distillation (b.p. 170° C./0.5 mm Hg).
Reaction SMILES: [O:1]=[C:2]1[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:5](=[O:12])[CH2:4][S:3]1.[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=3)[C:21]([I:30])=[N:20]2)=[C:16]([C:33]([F:36])([F:35])[F:34])[CH:15]=1>>[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:28]=[C:4]4/[C:5](=[O:12])[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:2](=[O:1])[S:3]/4)=[CH:25][CH:26]=3)[C:21]([I:30])=[N:20]2)=[C:16]([C:33]([F:36])([F:35])[F:34])[CH:15]=1
Reactant: O=Cc1ccc2c(c1)c(I)nn2Cc1ccc(Cl)cc1C(F)(F)F
Reactant: CS(=O)(=O)NN1C(=O)CSC1=O
Product: CS(=O)(=O)NN1C(=O)S/C(=C\c2ccc3c(c2)c(I)nn3Cc2ccc(Cl)cc2C(F)(F)F)C1=O

Procedure:
N-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-iodo-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from N-(2,4-dioxothiazolidin-3-yl)methanesulfonamide (from Example 360) and 1-[4-chloro-2-(trifluoromethyl)benzyl]-3-iodo-1H-indazol-5-carbaldehyde following General Procedure F.
Reaction SMILES: [CH3:1][Sn:2]([CH3:15])([CH3:14])[C:3]1[CH:12]=[N:11][C:10]2[NH:9][C:8](=[O:13])[CH2:7][O:6][C:5]=2[CH:4]=1.[Li]N([Si](C)(C)C)[Si](C)(C)[CH3:19].COS(OC)(=O)=O>C1COCC1>[CH3:19][N:9]1[C:8](=[O:13])[CH2:7][O:6][C:5]2[CH:4]=[C:3]([Sn:2]([CH3:15])([CH3:14])[CH3:1])[CH:12]=[N:11][C:10]1=2
Reactant: C[Sn](C)(C)c1cnc2c(c1)OCC(=O)N2
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: CN1C(=O)COc2cc([Sn](C)(C)C)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 680 mg of 7-trimethylstannyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (0.0022 mole) in 10 ml of THF is added 2.4 ml of LiN(TMS)2 (0.0024 mole) in THF. The homogenous solution is maintained under nitrogen at room temperature for 20 min., 300 mg (0.0024 mole) of dimethylsulfate is added and the reaction mixture allowed to stir overnight. The reaction mixture is then quenched with 10 ml of sat. ammonium chloride and extracted with 3×50 ml ethyl acetate. The ethyl acetate is then washed with 3×10 ml sat. ammonium chloride, dried over sodium sulfate and concentrated to obtain off white product which is used directly in the next step.
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[C:15]([CH3:28])[CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:38]1[CH:43]=[CH:42][N:41]([CH:44]2[CH2:46][CH2:45]2)[C:40](=[O:47])[CH:39]=1>>[CH:44]1([N:41]2[CH:42]=[CH:43][C:38]([C:16]3[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:36])[CH3:35])([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:14][C:15]=3[CH3:28])=[CH:39][C:40]2=[O:47])[CH2:46][CH2:45]1
Reactant: O=c1cc(Br)ccn1C1CC1
Reactant: Cc1cc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)ccc1B1OC(C)(C)C(C)(C)O1
Product: Cc1cc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)ccc1-c1ccn(C2CC2)c(=O)c1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methyl-propyl)-3-{(S)-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one and 4-bromo-1-cyclopropyl-1H-pyridin-2-one following a procedure analogous to that described in Step 5 of Example 96. LC-MS (Method 5): tR=3.42 min; Mass spectrum (ESI+): m/z=501 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(CC)CC)C>O1CCOCC1>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:10]([CH3:9])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:7]=1
Reactant: CCOC(=O)CNC
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)CN(C)c1nccc(Cl)n1

Procedure:
30.0 g (0.20 mol) of 2,4-dichloropyrimidine, 30.9 g (0.20 mol) of ethyl N-methylglycinate and 61.0 g (0.60 mol) of triethylamine in 200 ml of dioxane are stirred at 50° C. for 10 min. The mixture is filtered off with suction and the mother liquor is concentrated to half the original volume. A solid crystallizes out, which is filtered off with suction. The mother liquor is concentrated, the residue is stirred with petroleum ether and the product is filtered off.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:20]=[CH:19][C:12]([CH:13]=[C:14]([C:17]#[N:18])[C:15]#[N:16])=[CH:11][CH:10]=2)[CH2:4][O:3]1.[C:22]([CH2:24][C:25]([NH2:27])=[S:26])#[N:23].CN1CCOCC1>C(O)C>[NH2:18][C:17]1[C:14]([C:15]#[N:16])=[C:13]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH:5]3[CH2:4][O:3][C:2]([CH3:21])([CH3:1])[O:6]3)=[CH:20][CH:19]=2)[C:24]([C:22]#[N:23])=[C:25]([SH:26])[N:27]=1
Reactant: N#CCC(N)=S
Reactant: CC1(C)OCC(COc2ccc(C=C(C#N)C#N)cc2)O1
Solvent: CN1CCOCC1
Solvent: CCO
Product: CC1(C)OCC(COc2ccc(-c3c(C#N)c(N)nc(S)c3C#N)cc2)O1

Procedure:
0.43 g (1.51 mmol) of the compound from Example 2A, 0.38 g (3.78 mmol) of cyanothioacetamide and 0.38 g (3.78 mmol) of 4-methylmorpholine are dissolved in 15 ml of ethanol, and the mixture is stirred under reflux for 6 h. After cooling, the reaction solution is concentrated using a rotary evaporator, and the residue is chromatographed on silica gel 60. After removal of by-products (mobile phase gradient cyclohexane→cyclohexane/ethyl acetate 1:1), the product fractions are eluted (mobile phase gradient ethyl acetate→ethyl acetate/methanol 20:1). This is followed by fine purification via preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1>>[C:30]([O:29][C:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:16][CH:17]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(Cn2ccc3cc(C(=O)O)ccc32)cc1

Procedure:
The title compound was prepared following the same protocol as described in Step 2, Example 38, using 1H-indole-5-carboxylic acid instead of the methyl 1H-indole-5-carboxylate, and the tert-butyl 4′-(bromomethyl)biphenyl-2-carboxylate instead of the 1-bromo-4-(bromomethyl)benzene. ESI-MS (m/z): 428 [M+H]+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[CH2:33]([O:32][CH2:31][C@H:13]([NH:12][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)Cc1ccccn1
Agent: Cl
Product: O=C(Cc1ccccn1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 50 %

Procedure:
Proceeding as in Example 1, but substituting 2-(pyridin-2-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 246, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(pyridin-2-yl)acetamido)propanamide (3 mg, 50%). MS (EI) for C29H26FN3O4. found 500.5 (MH+).
Reaction SMILES: [Cl:1]N1C2C=CC=CC=2N=N1.[F:11][C:12]([F:29])([F:28])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:24]3[N:25]=[CH:26][CH:27]=[C:23]3[N:22]=[CH:21][CH:20]=2)[CH:14]=1.C(Cl)(Cl)Cl.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:27]1[CH:26]=[N:25][N:24]2[C:19]([C:15]3[CH:14]=[C:13]([C:12]([F:28])([F:11])[F:29])[CH:18]=[CH:17][CH:16]=3)=[CH:20][CH:21]=[N:22][C:23]=12
Reactant: Cln1nnc2ccccc21
Reactant: FC(F)(F)c1cccc(-c2ccnc3ccnn23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1cccc(-c2ccnc3c(Cl)cnn23)c1
Temperature: 25 °C

Procedure:
A 3.3 g. portion of N-chlorobenzotriazole is added to a solution of 5.26 g. of 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine in 50 ml. of chloroform producing an exothermic reaction. The mixture is refluxed on a steam bath for 15 minutes, cooled to room temperature and then poured into an ice-cold solution of 2.5 N sodium hydroxide. The organic layer is separated, dried over sodium sulfate and passed through a hydrous magnesium silicate column. The effluent is heated to reflux and hexane is added giving a solid. The solid is dissolved in methylene chloride re-processed through the column and precipitated from refluxing solution with hexane giving crystals of the desired product, m.p. 155°-157° C.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[N:16]1([CH2:22][CH2:23][CH2:24][C:25]2[N:26]=[N+:27]([O-:38])[C:28]3[CH:34]=[C:33]4[CH2:35][CH2:36][O:37][C:32]4=[CH:31][C:29]=3[N:30]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl>[N:16]1([CH2:22][CH2:23][CH2:24][C:25]2[N:26]=[N+:27]([O-:38])[C:28]3[CH:34]=[C:33]4[CH2:35][CH2:36][O:37][C:32]4=[CH:31][C:29]=3[N+:30]=2[O-:4])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: [O-][n+]1nc(CCCN2CCOCC2)nc2cc3c(cc21)CCO3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [O-][n+]1nc(CCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)CCO3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 42 %

Procedure:
H2O2 (70%, 0.31 mL, ca. 6.3 mmol) was added dropwise to a stirred solution of TFAA (0.88 mL, 6.3 mmol) in DCM (12 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. The solution was added to a solution of 1-oxide 215 (200 mg, 0.63 mmol) and TFA (0.10 mL, 1.4 mmol) in DCM (12 mL) at 0° C. and the solution was stirred at 20° C. for 2.5 h. Dilute aqueous NH3 solution was added until the mixture was basic and then the mixture was extracted with CHCl3 (3×20 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (1-5%) of MeOH/DCM, to give 1,4-dioxide 216 (88 mg, 43%) as a dark yellow solid: mp 150-154° C.; 1H NMR δ 8.28 (t, J=1.6 Hz, 1H, H-9), 7.68 (s, 1H, H-5), 4.87 (t, J=8.5 Hz, 2H, H-7), 3.48 (dt, J=8.5, 1.5 Hz, 2H, H-8), 3.44 (t, J=4.4 Hz, 4H, 2×CH2O), 3.22 (t, J=7.2 Hz, 2H, CH2), 2.49 (t, J=6.5 Hz, 2H, CH2), 2.38 (t, J=4.4 Hz, 4H, 2×CH2N), 2.06-2.13 (m, 2H, CH2); 13C NMR δ 166.7, 156.1, 141.7, 136.3, 130.2, 117.8, 96.1, 73.5, 67.0 (2), 58.0, 53.5 (2), 29.0, 28.8, 21.8. Anal. calcd for C16H20N4O4: C, 57.8; H, 6.1; N, 16.9. Found: C, 57.8; H, 6.1; N, 16.6%.
Reaction SMILES: [NH2:1][C:2](=[O:11])[CH2:3][C:4]([CH3:10])([CH3:9])[CH2:5][C:6]([OH:8])=[O:7].[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[NH2:1][C:2](=[O:11])[CH2:3][C:4]([CH3:9])([CH3:10])[CH2:5][C:6]([O:8][CH3:12])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(CC(N)=O)CC(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CC(C)(C)CC(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-3,3-dimethyl-5-oxopentanoic acid (10.9 g; 68.6 mmoles) was dissolved in DMF (50 mL). Potassium carbonate (14.2 g; 103 mmoles) and methyl iodide (8.5 mL; 137.2 mmoles) were added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered, washing the filter cake with DMF. The DMF was removed under vacuum and the residue was suspended in ethyl acetate. The solids were removed by filtration and the ethyl acetate was removed under vacuum to give the product, methyl 5-amino-3,3-dimethyl-5-oxopentanoate, as a yellow oil (11.5 g; 97%). 1H NMR (400 MHz) DMSO-d6 δ 7.22 (1H, s, br), 6.73 (1H, s, br), 3.58 (3H, s), 2.39 (2H, s), 2.09 (2H, s), 1.02 (6H, s).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:11]([Cl:22])[CH:10]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:11]([Cl:22])[CH:10]=1
Reactant: C=Cc1cc(CNC(=O)OC(C)(C)C)cc(Cl)c1NS(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=Cc1cc(CN)cc(Cl)c1NS(C)(=O)=O
Reaction time: 12 h
Yield: 142.3 %

Procedure:
(3-Chloro-4-methanesulfonylamino-5-vinylbenzyl)carbamic acid tert-butyl ester (30.7 mg, 0.09 mmol) and CF3COOH (5-6 drops) was added into methylene chloride. The reaction mixture was stirred for 12 hr. The reaction mixture was concentrated in vacuo to give a title compound (33.4 mg, 100%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[CH2:13]1[O:16][CH:14]1[CH3:15]>O1CCCC1>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:13][CH:14]([OH:16])[CH3:15])=[CH:6][CH:5]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: CC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)Cn1ccc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a stirred suspension of sodium hydride (60%, 1.26 g, 31.6 mmol) in tetrahydrofuran (30 mL) at 0° C. under Ar was added dropwise a solution of 6-chloroindole (4.0 g, 26 mmol) in tetrahydrofuran (30 mL). The mixture was stirred for 1 h and (RS)-propylene oxide (3.7 mL, 53 mmol) was added. The mixture was warmed to room temperature, stirred for 48 h and partitioned between aqueous ammonium chloride solution (100 mL) and ether (3×100 mL). The combined organic extracts were washed with brine (2×100 mL), dried (magnesium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; ethyl acetate-hexane (1:9)] to give the product (2.78 g, 50% yield) as a pale yellow oil. Data for the compounds produced using General Method A, step (a) are listed in Table 3.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.[CH3:21][N:22]1[C:27]2[CH:28]=[C:29]([NH2:32])[CH:30]=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:32][C:29]3[CH:30]=[CH:31][C:26]4[O:25][CH2:24][CH2:23][N:22]([CH3:21])[C:27]=4[CH:28]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: CN1CCOc2ccc(N)cc21
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4c(c3)N(C)CCO4)nn12

Procedure:
The titled compound was prepared in analogous fashion as Example 113 using 2-methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine and 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylamine to give 645 [7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-amine as a brown lyophilate. LCMS (E/I+) 388 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.88 (d, 1H, J=7.5 Hz), 7.27 (t, 1H, J=8 Hz), 7.04 (m, 3H), 6.95 (d, 1H, J=3.6 Hz), 6.81 (d, 1H, J=3.8 Hz), 6.72 (d, 1H, J=8.5 Hz), 6.65 (m, 2H), 4.24 (s, 2H), 3.81 (s, 3H), 3.20 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[N:10][N:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[C:21](=[O:27])[C:22](=[O:26])[C:23]=1OC>CO>[NH2:19][C:20]1[C:21](=[O:27])[C:22](=[O:26])[C:23]=1[NH:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][N:11]1[CH:12]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=[N:10]1
Reactant: COc1c(N)c(=O)c1=O
Reactant: NCCCCOn1cc(CN2CCCCC2)cn1
Solvent: CO
Product: Nc1c(NCCCCOn2cc(CN3CCCCC3)cn2)c(=O)c1=O
Temperature: 20 °C
Reaction time: 12 h

Procedure:
2.5 g of 4-(4-piperidinomethylpyrazol-1-yloxy)butylamine and 1.2 g of 3-amino-4-methoxycyclobutene-1,2-dione are introduced into 80 ml of methanol, and the mixture is stirred for 12 hours at 20° C. The solid formed is then filtered off under suction.